KR20050044816A - 6-0-substituted ketolides having antibacterial activity - Google Patents

Abstract

Antimicrobial compounds having formula (II), (III), (IV), (IV-A) or (V) as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compunds.

Description

6-O-substituted ketolides having antibacterial activity

This application is a partial consecutive application of US patent application Ser. No. 08 / 707,776, filed Sep. 4, 1996 and currently pending.

The present invention relates to novel semisynthetic macrolides having antimicrobial activity, pharmaceutical compositions comprising these compounds and methods of medical treatment. More particularly, the present invention relates to 6-O-substituted erythromycin ketolide derivatives, compositions containing these compounds, and methods of treating bacterial infections.

Erythromycin A to D of Formula 1 are potent antimicrobial agents well known to be widely used to treat and prevent bacterial infections.

However, as in the case of other antimicrobials, bacterial strains have been identified that are resistant to or lack susceptibility to erythromycin. In addition, erythromycin A shows only weak activity against Gram-negative bacteria. Thus, there is an ongoing need to identify new erythromycin derivative compounds that have enhanced antimicrobial activity, are less likely to become resistant, possess desired Gram negative activity, or have unexpected selectivity for target microorganisms. do. As a result, many researchers have prepared chemical derivatives of erythromycin to obtain homologues with improved or enhanced antimicrobial activity profiles.

US Pat. No. 5,444,051 describes 6-O-substituted-3-oxoerythromycin A derivatives, wherein the substituents are selected from alkyl, -CONH ₂ , -CONHC (O) alkyl and -CONHSO ₂ alkyl. . PCT WO 97/10251 (published March 20, 1997) describes 6-O-methyl 3-desladinos erythromycin derivatives.

EP-A 596802 (published May 11, 1994) describes bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.

PCT WO 92/09614 (published June 11, 1992) describes tricyclic 6-O-methylerythromycin A derivatives.

The present invention provides a new class of 6-O-substituted erythros with increased acid stability and enhanced activity against gram negative bacteria and macrolide-resistant gram positive bacteria compared to erythromycin A and 6-O-methyl erythromycin A. Provides a mycin derivative.

In one embodiment, the present invention provides a compound selected from the group consisting of the following Formulas 2, 3, 4, 4a and 5, or a pharmaceutically acceptable salt, ester or prodrug thereof:

In the above formula 2 to 5,

Y and Z together group X

{here,

X is (1) = O,

    (2) = N-OH,

(3) = NOR ¹ [where R ¹ is

(a) unsubstituted C ₁ -C ₁₂ -alkyl,

(b) C ₁ -C ₁₂ -alkyl substituted with aryl,

(c) C ₁ -C ₁₂ -alkyl substituted with substituted aryl,

(d) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

(e) C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl,

(f) C ₃ -C ₁₂ -cycloalkyl, and

(g) -Si- (R ² ) (R ³ ) (R ⁴ ) wherein R ² , R ³ and R ⁴ are each C ₁ -C ₁₂ -alkyl and

         Selected independently from aryl)

         Becomes] and

(4) = NOC (R ⁵ ) (R ⁶ ) -OR ¹ , wherein R ¹ is as defined above and R ⁵ and

R ⁶ is

        (a) hydrogen,

(b) unsubstituted C ₁ -C ₁₂ -alkyl,

(c) C ₁ -C ₁₂ -alkyl substituted with aryl,

(d) C ₁ -C ₁₂ -alkyl substituted with substituted aryl,

(e) C ₁ -C ₁₂ -alkyl substituted with heteroaryl and

(f) a group consisting of C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl

Each independently selected, or R ⁵ and R ⁶ are each independently selected from

Together to form a C ₃ -C ₁₂ -cycloalkyl ring];

       Selected}, or

One of Y and Z is hydrogen and the other is

   (1) hydrogen,

   (2) hydroxy,

   (3) protected hydroxy and

(4) NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are independently selected from hydrogen and C ₁ -C ₆ -alkyl

Or R ⁷ and R ⁸ , together with the nitrogen atom to which they are linked, are 3-membered to

    Forms a 7-membered ring, and when such a ring is 5- to 7-membered, -O-, -NH-,

-N (C ₁ -C ₆ - alkyl -) -, -N (aryl) -, -N (aryl -C ₁ -C ₆ - alkyl -) -, -N (substituted-aryl -C ₁

-C ₆ -alkyl-)-, -N (heteroaryl)-, -N (heteroaryl-C ₁ -C ₆ -alkyl-)-, -N (substituted

-Heteroaryl-C ₁ -C ₆ -alkyl-)-and -S- or -S (O) _n- , where n is 1 or 2

   Optionally contain a heterofunctional group selected from the group consisting of:

   It can be selected from the group consisting of

R ^a is hydrogen or hydroxy,

R ^b is selected from the group consisting of hydroxy, -OC (O) -NH ₂ and -OC (O) -imidazolyl,

R ^c is hydrogen or a hydroxy protecting group,

L is methylene or carbonyl, provided that when L is methylene, T is -O-,

T is -O-, -NH-, and -N (WR ^d )-

{Where W is absent or is selected from the group consisting of -O-, -NH-CO-, -N = CH- and -NH-,

R ^d is

  (1) hydrogen,

  (2) (a) aryl,

     (b) substituted aryl,

     (c) heteroaryl,

     (d) substituted heteroaryl,

     (e) hydroxy,

(f) C ₁ -C ₆ -alkoxy,

(g) NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above; and

(h) -CH ₂ -MR ⁹ where M is

      (Iii) -C (O) -NH,

      (Ii) -NH-C (O)-,

      (Iii) -NH-,

      (Iii) -N =,

(Iii) -N (CH ₃ )-,

      (Iii) -NH-C (O) -O-,

      (Iii) -NH-C (O) -NH-,

      (Iii) -O-C (O) -NH-,

      (Iii) -O-C (O) -O-,

      (Iii) -O-,

(Iii) -S (O) _n- , where n is 0, 1 or 2,

      (Vi) -C (O) -O-,

      (Iii) -O-C (O)-and

      (Iii) is selected from the group consisting of -C (O)-,

R ⁹ is

      (Iii) (aa) aryl, (bb) substituted aryl, (cc) heteroaryl, and (dd) substituted

        Optionally a substituent selected from the group consisting of heteroaryl

Substituted C ₁ -C ₆ -alkyl,

      (Ii) aryl,

      (Iii) substituted aryl,

      (Iii) heteroaryl,

      (Iii) substituted heteroaryl and

      (Iii) from the group consisting of heterocycloalkyl]

C ₁ -optionally substituted with one or more substituents selected from the group

C ₆ -alkyl,

(3) C ₃ -C ₇ -cycloalkyl,

  (4) aryl,

  (5) substituted aryl,

  (6) heteroaryl and

  (7) selected from the group consisting of substituted heteroaryl;

R is

  (1) (a) CN,

     (b) F,

(c) —CO ₂ R ¹⁰ wherein R ¹⁰ is C ₁ -C ₃ -alkyl or aryl substituted C ₁ -C ₃ -alkyl,

Or heteroaryl substituted C ₁ -C ₃ -alkyl;

(d) S (O) _n R ¹⁰ , wherein n is 0, 1 or 2, and R ¹⁰ is as defined above

      same],

(e) NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above;

(f) NHC (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are hydrogen, C ₁ -C ₃ -alkyl, aryl

Substituted C ₁ -C ₃ -alkyl, substituted aryl, heteroaryl and substituted heteroaryl

      Is independently selected from

     (g) aryl,

     (h) substituted aryl,

     (i) heteroaryl and

     (j) substituted heteroaryl

     Methyl substituted with a moiety selected from the group consisting of

(2) C ₂ -C ₁₀ -alkyl,

  (3) (a) halogen,

     (b) hydroxy,

(c) C ₁ -C ₃ -alkoxy,

(d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,

     (e) oxo,

(f) -N ₃ ,

     (g) -CHO,

(h) O-SO _2- (substituted C ₁ -C ₆ -alkyl),

(i) -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are

      (Iii) hydrogen,

(Ii) C ₁ -C ₁₂ -alkyl,

(Iii) substituted C ₁ -C ₁₂ -alkyl,

(Iii) C ₁ -C ₁₂ -alkenyl,

(Iii) substituted C ₁ -C ₁₂ -alkenyl,

(Iii) C ₁ -C ₁₂ -alkynyl,

(Iii) substituted C ₁ -C ₁₂ -alkynyl,

      (Iii) aryl,

(Iii) C ₃ -C ₈ -cycloalkyl,

(Iii) substituted C ₃ -C ₈ -cycloalkyl,

      (Iii) substituted aryl,

      (Vi) heterocycloalkyl,

      (Iii) substituted heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with aryl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted aryl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with C ₃ -C ₈ -cycloalkyl

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted C ₃ -C ₈ -cycloalkyl,

      (Iii) heteroaryl,

      (Iii) substituted heteroaryl,

(Vi) C ₁ -C ₁₂ -alkyl substituted with heteroaryl and

(Iii) a group consisting of C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl

              Selected from

R ¹³ and R ¹⁴ together with the atoms to which they are attached,

      (Iii) halogen,

      (Ii) hydroxy,

(Iii) C ₁ -C ₃ -alkoxy,

(Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,

      (Iii) oxo,

(Iii) C ₁ -C ₃ -alkyl,

(Iii) halo-C ₁ -C ₃ -alkyl and

(Iii) independently from the group consisting of C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl

      3- to 10-membered heterocycles that may be substituted with one or more substituents selected

      Forms a chloroalkyl ring],

(j) -CO ₂ R ¹⁰ wherein R ¹⁰ is as defined above;

(k) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

(l) = NOR ¹⁰ where R ¹⁰ is as defined above;

     (m) -C ≡N,

(n) OS (O) _n R ¹⁰ where n is 0, 1 or 2, and R ¹⁰ is as defined above

        same],

     (o) aryl,

     (p) substituted aryl,

     (q) heteroaryl,

     (r) substituted heteroaryl,

(s) C ₃ -C ₈ -cycloalkyl,

(t) substituted C ₃ -C ₈ -cycloalkyl,

(u) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

     (v) heterocycloalkyl,

     (w) substituted heterocycloalkyl,

(x) NHC (O) R ¹⁰ wherein R ¹⁰ is as defined above;

(y) NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

(z) = N-NR ¹³ R ¹⁴ where R ¹³ and R ¹⁴ are as defined above;

(aa) = NR ⁹ where R ⁹ is as defined above;

(bb) = N-NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above; and

(cc) = N-NHC (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above C ₂ -C ₁₀ -alkyl substituted with one or more substituents selected from the group consisting of:

  (4) (a) halogen,

     (b) -CHO,

(c) -CO ₂ R ¹⁰ , wherein R ¹⁰ is as defined above;

(d) -C (O) -R ⁹ , wherein R ⁹ is as defined above;

(e) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

     (f) -C ≡N,

     (g) aryl,

     (h) substituted aryl,

     (i) heteroaryl,

     (j) substituted heteroaryl,

(k) C ₃ -C ₇ -cycloalkyl and

(l) selected from the group consisting of C ₁ -C ₁₂ -alkyl substituted with heteroaryl

C ₃ -alkenyl substituted with residues,

(5) C ₄ -C ₁₀ -alkenyl,

  (6) (a) halogen,

(b) C ₁ -C ₃ -alkoxy,

     (c) oxo,

     (d) -CHO,

(e) -CO ₂ R ¹⁰ , wherein R ¹⁰ is as defined above;

(f) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

(g) —NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are as defined above;

(h) = NOR ¹⁰ where R ¹⁰ is as defined above;

     (i) -C ≡N,

(j) OS (O) _n R ¹⁰ where n is 0, 1 or 2, and R ¹⁰ is as defined above

         same],

     (k) aryl,

     (l) substituted aryl,

     (m) heteroaryl,

     (n) substituted heteroaryl,

(o) C ₃ -C ₇ -cycloalkyl,

(p) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

(q) NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above;

(r) NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

(s) = N-NR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are as defined above;

(t) = NR ⁹ where R ⁹ is as defined above;

(u) = N-NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above; and

(v) = N-NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

C ₄ -C ₁₀ -substituted with one or more substituents selected from the group consisting of

    Alkenyl,

(7) C ₃ -C ₁₀ -alkynyl and

  (8) (a) trialkylsilyl,

     (b) aryl,

     (c) substituted aryl,

     (d) heteroaryl and

     (e) one or more selected from the group consisting of substituted heteroaryls

Selected from the group consisting of C ₃ -C ₁₀ -alkynyl substituted with substituents,

A, B, D and E

  (a) hydrogen,

  (b) (iii) aryl,

      (Ii) substituted aryl,

      (Iii) heteroaryl,

      (Iii) substituted heteroaryl,

      (Iii) heterocycloalkyl,

      (Iii) hydroxy,

(Iii) C ₁ -C ₆ -alkoxy,

      (Iii) halogen consisting of Br, Cl, F or I and

(Iii) NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above;

C ₁ -C ₆ -al optionally substituted with one or more substituents selected from the group

      Kill,

(c) C ₃ -C ₇ -cycloalkyl,

  (d) aryl,

  (e) substituted aryl,

  (f) heteroaryl,

  (g) substituted heteroaryl,

  (h) heterocycloalkyl and

(i) further substituted with -MR ⁹ , wherein M and R ⁹ are as defined above;

    Independently selected from the group consisting of groups selected from (b) above, provided that at least two of A, B, D and E are hydrogen,

One of the substituent pairs consisting of AB, AD, AE, BD, BE and DE, together with the atom (s) to which they are attached, is -O-, -NH-, -N (C ₁ -C ₆ -alkyl-)- , -N (aryl-C ₁ -C ₆ -alkyl-)-, -N (substituted aryl-C ₁ -C ₆ -alkyl-)-, -N (heteroaryl-C ₁ -C ₆ -alkyl-) -, -N (substituted heteroaryl-C ₁ -C ₆ -alkyl-)-, -S- or -S (O) _n- , where n is 1 or 2; -C (O) -NH -, -C (O) -NR ^12- , where R ¹² is as defined above, -NH-C (O)-, -NR ¹² -C (O)-[where R ¹² is as defined above Equals] and -C (= NH) -NH- to form a 3- to 7-membered ring optionally containing a heterofunctional group selected from the group consisting of:

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as defined above together with a pharmaceutically acceptable carrier.

Further, the present invention relates to a method of treating a bacterial infection in such a host mammal, comprising administering a therapeutically effective amount of a compound as defined above to a mammal in need of treating the bacterial infection.

In a further aspect of the invention, there is provided a process for the preparation of 6-O-substituted macrolide derivatives of formulas 2, 3, 4, 4a and 5 above.

In one embodiment, the present invention provides a compound of Formula 2:

Formula 2

In Formula 2 above,

X, Y, R, R ^a and R ^c are as defined above.

Representative compounds of formula (2) are compounds wherein R ^a is OH, R ^c is benzoyl and R is allyl.

A preferred embodiment of the compound of formula 2 according to the invention is a compound wherein R ^a is hydroxy and R ^c is hydrogen.

A more preferred embodiment of the compound of formula 2 according to the invention is a compound of formula

In Formula 8 above,

X is O or NOH,

R is as defined above.

Representative compounds of this embodiment include, but are not limited to:

A compound of Formula 8 wherein X is O and R is allyl;

A compound of Formula 8 wherein X is NOH and R is allyl;

A compound of Formula 8 wherein X is O and R is propyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CHO;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = NOH;

A compound of Formula 8 wherein X is NOH and R is -CH ₂ CH = NOH;

A compound of Formula 8 wherein X is O and R is -CH ₂ CN;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NH ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH (CO ₂ CH ₃ ) CH ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH _2- (4-pyridyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH _2- (4-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH-phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CH ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (4-methoxyphenyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (4-chlorophenyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CH ₂ OH;

A compound of Formula 8 wherein X is O and R is -CH ₂ C (O) OH;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ NHCH ₂ OH;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ N (CH ₃ ) ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ (1-morpholinyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ C (O) NH ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ NHC (O) NH ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ NHC (0) CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ F;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ OCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH (CH ₃ ) ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CH (CH ₃ ) CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ OCH ₂ CH ₂ OCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ SCH ₃ ;

A compound of Formula 8 wherein X is O and R is -cyclopropyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ OCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ F;

A compound of Formula 8 wherein X is O and R is -CH ₂ -cyclopropyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CHO;

A compound of Formula 8 wherein X is O and R is -C (O) CH ₂ CH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH _2- (4-nitrophenyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (4-chlorophenyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (4-methoxyphenyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (4-cyanophenyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHC (O) OCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHC (O) OCH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHCH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHCH ₂ CH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHSO ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ C≡C-Si (CH ₃ ) ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ C≡CCH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ C≡CCH ₃ ;

X is O and R is -CH ₂ -, a compound of formula (8) (2-pyridyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (3-pyridyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (4-pyridyl);

A compound of Formula 8 wherein X is O and R is -CH _2- (4-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ NO ₂ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ C (O) OCH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ C (O) -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ C (O) CH ₂ CH ₃ ;

A compound of Formula 8 wherein X is O and R is -CH ₂ Cl;

A compound of Formula 8 wherein X is O and R is -CH ₂ S (O) ₂ -phenyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CHBr;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (4-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CH _2- (4-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (5-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH ₂ CH _2- (5-quinolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (4-benzoxazolyl);

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH- (7-benzimidazolyl);

A compound of Formula 8 wherein X is O and R is CH _2- (3-iodophenyl);

X is O and R is CH ₂ - A compound of formula (8) (2-naphthyl);

A compound of Formula 8 wherein X is O and R is CH ₂ -CH = CH- (4-fluorophenyl); And

A compound of formula 8 wherein X is O and R is CH ₂ -CH (OH) -CN.

Preferred compounds of formula (8)

A compound of Formula 8 wherein X is O and R is allyl;

A compound of Formula 8 wherein X is O and R is -CH ₂ CH = CH-phenyl; And

And X is O and R is -CH ₂ CH = CH- (3-quinolyl).

In one aspect, the invention

Chemical formula

Compound of

Wherein R ^p is a hydroxy protecting group and V is = NOR ¹ or = NOC (R ⁵ ) (R ⁶ ) -OR ¹ , wherein R ¹ , R ⁵ and R ⁶ are as defined above] Is treated with a base in an aprotic solvent and then with an alkylating agent to

Compound of

Where R ^a and R ^p are as defined above and V is = NOR ¹ or = NOC (R ⁵ ) (R ⁶ ) -OR ¹ , where R ¹ , R ⁵ and R ⁶ are as defined above R is an "alkyl group" derived from the corresponding alkylating agent] (a),

By deprotecting the 2'- and 4 "-hydroxy groups

Compound of

(B) obtaining (wherein R ^a is as defined above and R is an "alkyl group" derived from the corresponding alkylating agent),

The desired chemical formula by deoxime in a suitable solvent in the presence of an acid

Intermediates

Obtaining (c),

Hydrolysis with an acid to remove the cladinose residue and treatment with a hydroxy protection reagent to protect the 2'-hydroxyl group

(D) obtaining a 3-hydroxy erythromycin compound of

Oxidizing the 3-hydroxy group, optionally deprotecting the 2'-hydroxyl group and then separating the desired compound, thereby eliminating the 6-O-substituted macrolide compound Methods of making are provided:

Formula 2

In Formula 2 above,

Y, Z, R ^a , R ^c and R are as defined above.

In a preferred embodiment of the process, in step (a), the base is potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide and potassium isobu The alkylating agent is allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, α-bromine Mo-p-tolunitrile, cinnamil bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo- 1-trimethylsilyl-1-propine, 3-bromo-2-octin, 1-bromo-2-butyne, 2-picolyl chloride, 3-picolyl chloride, 4-picolyl chloride, 4-bromo Methyl quinoline, bromoacetonitrile , Epichlorohydrin, bromofluoromethane, bromoniromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, bro Parent chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-propene, allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate and n-butyl-O-methane Selected from the group consisting of sulfonates; The reaction is carried out at about −15 ° C. to about 50 ° C. for 0.5 hours to 10 days; In step (b), the deprotection reaction is carried out using acetic acid in water and acetonitrile; In step (c), the deoxime agent consists of sodium bisulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate and potassium metabisulfite An inorganic sulfur oxide compound selected from the group or an inorganic nitrite salt in the presence of an acid, selected from the group consisting of sodium nitrite and potassium nitrite, the solvent being water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or mixtures of one or more thereof It is selected from the group consisting of; In step (d), the hydroxy protecting reagent is selected from the group consisting of trialkylsilyl halides, acyl anhydrides and acyl halides; In step (e), the oxidizing agent is selected from N-chlorosuccinimide-dimethyl sulfide and carbodiimide-dimethylsulfoxide and is carried out by stirring any deprotection reaction in methanol.

In another embodiment, the present invention provides a compound of formula

Formula 3

In Formula 3 above,

R, R ^c , L and T are as defined above.

Preferred compounds of formula 3

A compound of Formula 3 wherein R ^c is acetyl, L is CO, T is NH and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 3 wherein R ^c is acetyl, L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 3 wherein R ^c is benzoyl, L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 3 wherein R ^c is propanoyl, L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl); And

R ^c is ethylsuccinoyl, L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl).

A more preferred embodiment of the compound of formula 3 according to the invention is a compound of formula 9:

In Formula 9 above,

L, T and R are as defined above.

Representative compounds of this embodiment include, but are not limited to:

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH-phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (4-chlorophenyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH ₃ ;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ NH ₂ ;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = NOH;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH ₂ OH;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ F;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH (OH) CN;

A compound of Formula 9 wherein L is CO, T is O and R is -CH (C (O) 0CH ₃ ) CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CN;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (4-methoxyphenyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (4-fluorophenyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (8-quinolyl);

A compound of Formula 9 wherein L is CO and T is O and R is -CH ₂ CH ₂ NHCH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (5-quinolyl);

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH ₂ CH _2- (5-quinolyl);

A compound of Formula 9 wherein L is CO and T is O and R is -CH ₂ CH = CH- (4-benzoxazolyl);

A compound of Formula 9 wherein L is CO and T is O and R is -CH ₂ CH = CH- (4-benzimidazolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH-phenyl;

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH ₃ ;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NH ₂ ;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOH;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH ₂ OH;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ F;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH (OH) CN;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH (C (O) 0CH ₃ ) CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CN;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-chlorophenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-fluorophenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (4-methoxyphenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-methoxyphenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-chloro-6-quinolyl);

L is CO and T is NH, and R is _{-CH 2 CH 2 NHCH 2 CH 2} - (2- chlorophenyl) The compound of formula (9);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (4-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-fluoro-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-cyano-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (5-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-benzoxazolyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (4-benzimidazolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-methoxy-6-quinolyl);

L is CO and T is NH, and R is -CH ₂ -, a compound of formula (9) (2-naphthyl);

A compound of Formula 9 wherein L is CO, T is N (CH) ₃ and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is N (CH) ₃ and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) and R is -CH ₂ CH = CH- (3-quinolyl);

L is CO and T is _{N (CH 2 CH = CH 2} ) a compound of the formula R 9 is a -CH ₂ CH = CH _2;

A compound of Formula 9 wherein L is CO, T is N (CH ₂ CH = C- (3-quinolyl)) and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-isoquinolinyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (3,4-methylenedioxyphenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (8-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-indolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-chloro-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3,4-ethylenedioxyphenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-nitrophenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-nitroquinolinyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (2-methyl-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH, R ^c is acetyl and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-isoquinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (7-nitro-6-quinoxalinyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-amino-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (1,8-naphthyridin-3-yl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6- (acetylamino) -3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-carbazolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-benzimidazolyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (3-hydroxy-2- (N- (2-methoxyphenyl) amido) -7-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-quinoxalinyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-hydroxy-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-methoxy-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-nitro-3-quinolyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (8-nitro-3-quinolyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (2-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-carboxyl-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-fluoro-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-methoxycarbonyl-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-aminocarbonyl-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-cyano-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-bromo-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ C (O) H;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ phenyl;

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ CH ₂ phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH _2- (3-quinolyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH _2- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHCH _2- (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NO (phenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (phenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (4-NO ₂ -phenyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (2-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (3-quinolyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (1-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ NHOCH _2- (phenyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH ₂ NHOCH _2- (4-NO ₂ -phenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ C (O)-(phenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ C (O)-(4-F-phenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = NNHC (O) phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (3-quinolyl);

L is CO and T is NH, and R is -CH ₂ - (2- (3- quinolyl) cyclopropyl) compounds of formula (9);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡CH;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-nitro-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C-phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C-naphthyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (2-naphthyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ -C≡C- (6-methoxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-chloro-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (2-methyl-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (5- (N- (2-pyridyl) amino) carbonyl) furanyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (1-phenylethenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C-Br;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH _2- (2,2-dimethyl-1,3-dioxolan-4-yl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH (OH) -phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH (OH) CH ₂ OH;

A compound of Formula 9 wherein L is CO, T is NHNH ₂ and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is NHNH ₂ and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NHNH ₂ and R is -CH ₂ CH ₂ CH _2- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH-naphthyl;

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3- (2-furanyl) -6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (8-chloro-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (4-chloro-2-trifluoromethyl-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (9-fluorenon-2-yl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (6-benzoyl-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (7-methoxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3-phenyl-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3- (2-pyridyl) -6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3- (2-thiophenyl) -6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (4-methylnaphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is —CH ₂ CH═CH— (6-β-D-galactopyranosyl-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (7-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (4-fluoronaphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3-biphenyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (5-nitronaphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (4-pyrrolylphenyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (6-methoxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3,5-dichlorophenyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH _2- (3-iodophenyl);

L is CO and T is NH _2, and R is -CH ₂ - (3- (2- furanyl) phenyl) A compound of formula 9;

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (6-hydroxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (6- (2-bromoethoxy) -2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (6- (2- (tetrazolyl) ethoxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH-naphthyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ C≡C- (2-phenylethenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5- (3-isooxazolyl) -2-thiophenyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (1,3-dimethyl-2,4-dioxo-5-pyrimidinyl); and

A compound of formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (5- (2-pyridyl) aminocarbonyl-2-furanyl).

Preferred compounds of formula 9 are

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH-phenyl;

A compound of Formula 9 wherein L is CO, T is O and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH-phenyl;

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is N (CH ₃ ) and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is N (CH ₃ ) and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-pyridyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-isoquinolinyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (3,4-methylenedioxyphenyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (8-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-nitroquinolinyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-quinolyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-amino-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (1,8-naphthyridin-3-yl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6- (acetylamino) -3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-quinoxalinyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-hydroxy-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-methoxy-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (5-nitro-3-quinolyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ CH = CH- (8-nitro-3-quinolyl);

A compound of Formula 9, wherein L is CO, T is NH and R is -CH ₂ CH = CH- (2-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (4-carboxyl-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-fluoro-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-methoxycarbonyl-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-aminocarbonyl-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (6-cyano-3-quinolyl);

A compound of formula 9 wherein L is CO, T is NH and R is -CH ₂ CH = CH- (3-bromo-6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ CH ₂ CH _2- (3-quinolyl);

L is CO and T is NH, and R is -CH ₂ - (2- (3- quinolyl) cyclopropyl) compounds of formula (9);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡CH;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-nitro-3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C-phenyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C-naphthyl;

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (2-naphthyl);

A compound of Formula 9 wherein L is CO and T is NH and R is -CH ₂ -C≡C- (6-methoxy-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-chloro-2-naphthyl);

A compound of Formula 9 wherein L is CO, T is NH and R is -CH ₂ -C≡C- (6-quinolyl);

A compound of Formula 9 wherein L is CO, T is N (NH ₂ ) and R is -CH ₂ CH = CH ₂ ;

A compound of Formula 9 wherein L is CO, T is N (NH ₂ ) and R is -CH ₂ CH = CH- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is N (NH ₂ ) and R is -CH ₂ CH ₂ CH _2- (3-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH-naphthyl;

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (3- (2-pyridyl) -6-quinolyl);

A compound of Formula 9 wherein L is CO, T is NH ₂ and R is -CH ₂ CH = CH- (7-quinolyl); And

And L is CO and T is NH and R is -CH ₂ CH = CH- (5- (3-isooxazolyl) -2-thiophenyl).

In another aspect, the present invention

Chemical formula

Compound of

Wherein R is as defined below, R ^p is a hydroxy protecting group and Z 'is a 4 "-hydroxy protected cladinose, and is treated with sodium hexamethyldisilazide and carbonyldiimidazole.

Compound of

Obtaining (a),

The compound obtained from step (a) is treated with a reagent selected from the group consisting of ammonia, R ^e -NH ₂ , hydrazine, substituted hydrazine, hydroxylamine and substituted hydroxylamine

Compound of

[Where R ^e is H or WR ^d , W is absent or is selected from the group consisting of —O—, —NH—CO—, —N═CH— and —NH— and R ^d is Equal to] (b),

Optionally, the compound from step (b), wherein R ^e is H, is treated with an alkylating agent of the formula R ^d -halogen, where R ^d is as defined below, where R ^e is WR ^d and W is absent and R is absent. (c) obtaining a compound of the formula shown in step (b), wherein ^d is defined next,

Optionally, the compound from step (b) wherein R ^e is WR ^d and W is -NH- and R ^d is H is selected from the group consisting of the formula R ^d -halogen, wherein R ^d is as defined below; Treating with an alkylating agent to give a compound of the formula shown in step (b), wherein R ^e is WR ^d and W is -NH- and R ^d is defined as follows (d),

Optionally, the compound from step (b) wherein R ^e is WR ^d , W is -NH- and R ^d is H, is represented by the formula R ^d -C (CO) -halogen or (R ^d -C (CO) -O) ₂ Treating with acylation selected from the group consisting of R ^e is WR ^d and W is -NH-CO- and R ^d is as defined in (e),

Optionally, the compound from step (b) wherein R ^e is WR ^d , W is -NH- and R ^d is H is treated with an aldehyde of formula R ^d -CHO, where R ^d is as defined below. (F) obtaining a compound wherein R ^e is WR ^d and W is -N = CH- and R ^d is defined as

By removing hydrochloric acid residues by hydrolysis with acid

Obtaining a compound of (g),

Oxidizing the 3-hydroxyl group (h) and

Provided is a process for preparing a 6-O-substituted macrolide compound of the following formula, optionally comprising deprotection and then (i) isolating the desired compound:

In the above formula,

R is

  (1) (a) CN,

     (b) F,

(c) -CO ₂ R ¹⁰ , wherein R ¹⁰ is C ₁ -C ₃ -alkyl or aryl substituted C ₁ -C ₃ -alkyl, or heteroaryl substituted C ₁ -C ₃ -alkyl,

(d) S (O) _n R ¹⁰ where n is 0, 1 or 2 and R ¹⁰ is as defined above;

(e) NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above;

(f) NHC (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are hydrogen, C ₁ -C ₃ -alkyl, aryl

Independently selected from substituted C ₁ -C ₃ -alkyl, substituted aryl, heteroaryl and substituted heteroaryl],

     (g) aryl,

     (h) substituted aryl,

     (i) heteroaryl and

     (j) substituted heteroaryl

     Methyl substituted with a moiety selected from the group consisting of

(2) C ₂ -C ₁₀ -alkyl,

  (3) (a) halogen,

     (b) hydroxy,

(c) C ₁ -C ₃ -alkoxy,

(d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,

     (e) oxo,

(f) -N ₃ ,

     (g) -CHO,

(h) O-SO _2- (substituted C ₁ -C ₆ -alkyl),

(i) -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are

      (Iii) hydrogen,

(Ii) C ₁ -C ₁₂ -alkyl,

(Iii) substituted C ₁ -C ₁₂ -alkyl,

(Iii) C ₁ -C ₁₂ -alkenyl,

(Iii) substituted C ₁ -C ₁₂ -alkenyl,

(Iii) C ₁ -C ₁₂ -alkynyl,

(Iii) substituted C ₁ -C ₁₂ -alkynyl,

      (Iii) aryl,

(Iii) C ₃ -C ₈ -cycloalkyl,

(Iii) substituted C ₃ -C ₈ -cycloalkyl,

      (Iii) substituted aryl,

      (Vi) heterocycloalkyl,

      (Iii) substituted heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with aryl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted aryl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heterocycloalkyl,

(Iii) C ₁ -C ₁₂ -alkyl substituted with C ₃ -C ₈ -cycloalkyl

(Iii) C ₁ -C ₁₂ -alkyl substituted with substituted C ₃ -C ₈ -cycloalkyl,

      (Iii) heteroaryl,

      (Iii) substituted heteroaryl,

(Vi) C ₁ -C ₁₂ -alkyl substituted with heteroaryl and

(Iii) a group consisting of C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl

              Selected from

R ¹³ and R ¹⁴ together with the atoms to which they are attached,

      (Iii) halogen,

      (Ii) hydroxy,

(Iii) C ₁ -C ₃ -alkoxy,

(Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,

      (Iii) oxo,

(Iii) C ₁ -C ₃ -alkyl,

(Iii) halo-C ₁ -C ₃ -alkyl and

(Iii) independently from the group consisting of C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl

      3- to 10-membered heterocycles that may be substituted with one or more substituents selected

      Forms a chloroalkyl ring],

(j) -CO ₂ R ¹⁰ wherein R ¹⁰ is as defined above;

(k) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

(l) = NOR ¹⁰ where R ¹⁰ is as defined above;

     (m) -C ≡N,

(n) OS (O) _n R ¹⁰ where n is 0, 1 or 2, and R ¹⁰ is as defined above

        same],

     (o) aryl,

     (p) substituted aryl,

     (q) heteroaryl,

     (r) substituted heteroaryl,

(s) C ₃ -C ₈ -cycloalkyl,

(t) substituted C ₃ -C ₈ -cycloalkyl,

(u) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

     (v) heterocycloalkyl,

     (w) substituted heterocycloalkyl,

(x) NHC (O) R ¹⁰ wherein R ¹⁰ is as defined above;

(y) NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

(z) = N-NR ¹³ R ¹⁴ where R ¹³ and R ¹⁴ are as defined above;

(aa) = NR ⁹ where R ⁹ is as defined above;

(bb) = N-NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above; and

(cc) = N-NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

C ₂ -C ₁₀ -alkyl substituted with one or more substituents selected from the group consisting of

  (4) (a) halogen,

     (b) -CHO,

(c) -CO ₂ R ¹⁰ , wherein R ¹⁰ is as defined above;

(d) -C (O) -R ⁹ , wherein R ⁹ is as defined above;

(e) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

     (f) -C ≡N,

     (g) aryl,

     (h) substituted aryl,

     (i) heteroaryl,

     (j) substituted heteroaryl,

(k) C ₃ -C ₇ -cycloalkyl and

(l) selected from the group consisting of C ₁ -C ₁₂ -alkyl substituted with heteroaryl

C ₃ -alkenyl substituted with residues,

(5) C ₄ -C ₁₀ -alkenyl,

  (6) (a) halogen,

(b) C ₁ -C ₃ -alkoxy,

     (c) oxo,

     (d) -CHO,

(e) -CO ₂ R ¹⁰ , wherein R ¹⁰ is as defined above;

(f) —C (O) NR ¹¹ R ¹² wherein R ¹¹ and R ¹² are as defined above;

(g) —NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are as defined above;

(h) = NOR ¹⁰ where R ¹⁰ is as defined above;

     (i) -C ≡N,

(j) OS (O) _n R ¹⁰ where n is 0, 1 or 2, and R ¹⁰ is as defined above

         same],

     (k) aryl,

     (l) substituted aryl,

     (m) heteroaryl,

     (n) substituted heteroaryl,

(o) C ₃ -C ₇ -cycloalkyl,

(p) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,

(q) NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above;

(r) NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

(s) = N-NR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are as defined above;

(t) = NR ⁹ where R ⁹ is as defined above;

(u) = N-NHC (O) R ¹⁰ , wherein R ¹⁰ is as defined above; and

(v) = N-NHC (O) NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are as defined above;

C ₄ -C ₁₀ -alkenyl substituted with one or more substituents selected from the group consisting of

(7) C ₃ -C ₁₀ -alkynyl and

  (8) (a) trialkylsilyl,

     (b) aryl,

     (c) substituted aryl,

     (d) heteroaryl and

     (e) substituted heteroaryl

Is selected from the group consisting of C ₃ -C ₁₀ -alkynyl substituted with one or more substituents selected from the group consisting of

R ^e is H or WR ^d ,

W is absent or from the group consisting of -O-, -NH-CO-, -N = CH- and -NH-

 Selected,

R ^d is

  (1) hydrogen,

  (2) (a) aryl,

     (b) substituted aryl,

     (c) heteroaryl,

     (d) substituted heteroaryl,

     (e) hydroxy,

(f) C ₁ -C ₆ -alkoxy,

(g) NR ⁷ R ⁸ wherein R ⁷ and R ⁸ are independently selected from hydrogen and C ₁ -C ₆ -alkyl

Or R ⁷ and R ⁸ , together with the nitrogen atom to which they are attached, are 3-membered to

      Forms a seven-membered ring, and when the ring is 5- to 7-membered, -O-, -NH-,

-N (C ₁ -C ₆ - alkyl -) -, -N (aryl) -, -N (aryl -C ₁ -C ₆ - alkyl -) -, -N (substituted-aryl-

C ₁ -C ₆ -alkyl-)-, -N (heteroaryl)-, -N (heteroaryl-C ₁ -C ₆ -alkyl-)-, -N (value

Ring-heteroaryl-C ₁ -C ₆ -alkyl-)-, and -S- or -S (O) _n- , wherein n is 1 or

    Optionally is a heterofunctional group selected from the group consisting of

    Can be] and

(h) -CH ₂ -MR ⁹ where M is

      (Iii) -C (O) -NH,

      (Ii) -NH-C (O)-,

      (Iii) -NH-,

      (Iii) -N =,

(Iii) -N (CH ₃ )-,

      (Iii) -NH-C (O) -O-,

      (Iii) -NH-C (O) -NH-,

      (Iii) -O-C (O) -NH-,

      (Iii) -O-C (O) -O-,

      (Iii) -O-,

(Iii) -S (O) _n- , where n is 0, 1 or 2,

      (Vi) -C (O) -O-,

      (Iii) -O-C (O)-and

      (Iii) is selected from the group consisting of -C (O)-,

R ⁹ is

      (Iii) (aa) aryl, (bb) substituted aryl, (cc) heteroaryl, and (dd) substituted

        Optionally substituted with a substituent selected from the group consisting of heteroaryl

C ₁ -C ₆ -alkyl,

      (Ii) aryl,

      (Iii) substituted aryl,

      (Iii) heteroaryl,

      (Iii) substituted heteroaryl and

      (Iii) heterocycloalkyl]

     Optionally substituted with one or more substituents selected from the group consisting of:

Substituted C ₁ -C ₆ -alkyl,

(3) C ₃ -C ₇ -cycloalkyl,

  (4) aryl,

  (5) substituted aryl,

  (6) heteroaryl and

  (7) selected from the group consisting of substituted heteroaryls.

In a preferred embodiment of the above-mentioned process, R is 1-phenylethenyl, 2-chlorophenyl, 2-fluorenyl, 2-methyl-6-quinolyl, 2-naphthyl, 2-phenylethenyl, 2 -Quinolyl, 3- (2-furanyl) -6-quinolyl, 3- (2-pyridyl) -6-quinolyl, 3-quinolyl, 3- (2-thiophenyl) -6-quinolyl , 3-biphenyl, 3-bromo-6-quinolyl, 3-carbazolyl, 3-chloro-6-quinolyl, 3-cyano-6-quinolyl, 3-fluoro-6-quinolyl, 3-hydroxy-2- (N- (2-methoxyphenyl) amido) -7-naphthyl, 3-iodophenyl, 3-methoxy-6-quinolyl, 3-nitrophenyl, 3-phenyl -6-quinolyl, 3-quinolyl, 4-benzoxazolyl, 4-carboxy-3-quinolyl, 4-chloro-2-trifluoromethyl-6-quinolyl, 4-chlorophenyl, 4-fluoro Ronaphthyl, 4-fluorophenyl, 4-isoquinolinyl, 4-methoxyphenyl, 4-methylnaphthyl, 4-pyridyl, 4-pyrrolylphenyl, 4-quinolyl, 5- (2- Pyridyl) aminocarbonyl-2-furanyl, 5- (3-isooxazolyl) -2-thiophenyl, 5-benzimidazolyl, 5-indolyl, 5-isoqui Reyl, 5-nitro-3-quinolyl, 5-nitronaphthyl, 5- (N- (2-pyridyl) amino) carbonyl) furanyl, 5-quinolyl, 6- (acetylamino) -3- Quinolyl, 6- (2-tetrazolyl) ethoxy-2-naphthyl, 6- (2-bromoethoxy) -2-naphthyl, 6-amino-3-quinolyl, 6-aminocarbonyl-3 -Quinolyl, 6-β-D-galactopyranosyl-2-naphthyl, 6-benzoyl-2-naphthyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6 -Hydroxy-2-naphthyl, 6-hydroxy-3-quinolyl, 6-methoxy-2-naphthyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl , 6-nitroquinolyl, 6-quinolyl, 6-quinoxalinyl, 7-methoxy-2-naphthyl, 7-nitro-6-quinoxalinyl, 7-quinolyl, 8-chloro-3-qui Nolyl, 8-nitro-3-quinolyl, 8-quinolyl, 9-oxofluoren-2-yl, 1,3-dimethyl-2,4-dioxo-5-pyrimidinyl, 1,8-naphthy Allyl substituted with a residue selected from the group consisting of ridin-3-yl, 3,4-methylenedioxyphenyl, 3,5-dichlorophenyl, naphthyl and phenyl Propargyl group; In step (b), the reagent is selected from the group consisting of ammonia and R ^e -NH ₂ ; Optional step (c), step (d) and step (e) are omitted; In step (g), the oxidizing agent is selected from N-chlorosuccinimide-dimethyl sulfide and carbodiimide-dimethylsulfoxide; In step (h), any deprotection process is carried out by stirring in methanol.

In a more preferred embodiment of the aforementioned method, R is 2-methyl-6-quinolyl, 2-quinolyl, 3- (2-furanyl) -6-quinolyl, 3- (2-pyridyl)- 6-quinolyl, 3-quinolyl, 3- (2-thiophenyl) -6-quinolyl, 3-bromo-6-quinolyl, 3-chloro-6-quinolyl, 3-cyano-6- Quinolyl, 3-fluoro-6-quinolyl, 3-methoxy-6-quinolyl, 3-phenyl-6-quinolyl, 3-quinolyl, 4-carboxy-3-quinolyl, 4-chloro- 2-trifluoromethyl-6-quinolyl, 4-isoquinolinyl, 4-quinolyl, 5-isoquinolyl, 5-nitro-3-quinolyl, 5-quinolyl, 6- (acetylamino) 3-quinolyl, 6-amino-3-quinolyl, 6-aminocarbonyl-3-quinolyl, 6-cyano-3-quinolyl, 6-fluoro-3-quinolyl, 6-hydroxy -3-quinolyl, 6-methoxy-3-quinolyl, 6-methoxycarbonyl-3-quinolyl, 6-nitroquinolyl, 6-quinolyl, 7-quinolyl, 8-chloro-3- An allyl or propargyl group substituted with a residue selected from the group consisting of quinolyl, 8-nitro-3-quinolyl and 8-quinolyl .

In another aspect, the present invention

Chemical formula

Compound of

By treating with ozone

Obtaining a compound of (a),

(B) treating the compound of step (a) with a hydroxylamine compound of formula NH ₂ -OR ¹⁰ , wherein R ¹⁰ is as defined below; and

Provided is a process for preparing a compound of the formula: optionally deprotecting and then (c) isolating the desired compound:

In the above formula,

R ^e is H or WR ^d ,

W is absent or is selected from the group consisting of -O-, -NH-CO-, -N = CH- and -NH-,

R ^d is as defined above,

R ¹⁰ is H, C ₁ -C ₃ -alkyl, aryl substituted C ₁ -C ₃ -alkyl, or heteroaryl substituted C ₁ -C ₃ -alkyl.

In a preferred embodiment of the above method, R ^e is H.

In another aspect, the present invention

Chemical formula

(A) reductively aminating a compound of formula with an amine compound of formula NH ₂ -R ¹³ , wherein R ¹³ is as defined above; and

A method of preparing a compound of the formula is provided, including (b) optionally deprotecting and then separating the desired compound:

In the above formula,

R ^e is H or WR ^d ,

W is absent or is selected from the group consisting of -O-, -NH-CO-, -N = CH- and -NH-,

R ^d is as defined above.

In another embodiment, the present invention provides a compound of formula

Formula 4

In Formula 4 above,

R, R ^c , A, B, D and E are as defined above.

A preferred embodiment of the compound of formula 4 according to the invention is a compound of formula 7:

In Formula 7, above,

A, B, D, E and R are as defined above.

Representative compounds of Formula 7 in this embodiment include, but are not limited to:

A compound of formula 7 wherein A, B, D and E are H and R is allyl;

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH ₃ ;

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ NH ₂ ;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = NOH;

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH ₂ OH;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ F;

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CN;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH (OH) CN;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ -phenyl;

A compound of formula 7 wherein A, B, D and E are H and R is -CH _2- (4-pyridyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH _2- (4-quinolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-pyridyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-chlorophenyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-fluorophenyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-methoxyphenyl);

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH ₂ -phenyl;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-pyridyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH _2- (4-pyridyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-quinolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH _2- (4-quinolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (5-quinolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ CH _2- (5-quinolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-benzoxazolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (4-benzimidazolyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (8-quinolyl);

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ NHCH ₂ -phenyl;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ NHCH _2- (4-pyridyl);

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ NHCH _2- (4-quinolyl);

A compound of Formula 7 wherein A, B, D and E are H and R is -CH ₂ CH ₂ NHCH (CH ₂ -phenyl) C (O) OCH ₃ ;

A, B, and D and E are H R is _{-CH 2 CH 2 NHCH 2 CH 2} - A compound of formula 7 (2-chlorophenyl);

A compound of formula 7 wherein A, B and E are H, D is benzyl and R is allyl;

A compound of formula 7 wherein A is benzyl, B, D and E are H and R is allyl;

A compound of formula 7 wherein A and E are phenyl, B and D are H and R is allyl;

A compound of Formula 7 wherein A is methyl, B, D and E are H and R is allyl;

A compound of Formula 7 wherein A and D are methyl, B and E are H and R is allyl;

A compound of formula 7 wherein A and E together are —CH ₂ CH ₂ CH ₂ —, B and D are H and R is allyl;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (3-quinolyl); And

A compound of formula 7 wherein A, B, D and E are H and R is 3- (3-quinolyl) propyl.

Preferred compounds of formula (7)

A compound of formula 7 wherein A, B, D and E are H and R is allyl;

A compound of formula 7 wherein A, B, D and E are H and R is -CH ₂ CH = CH- (3-quinolyl); And

A, B, D and E are H and R is -CH ₂ CH ₂ CH _2- (3-quinolyl).

In another aspect, the present invention

The compound of formula 2 is then treated with methanesulfonic anhydride in pyridine and the methanesulfonyl derivative is treated with an amine base

Obtaining a compound of (a),

The compound from step (a) is treated with an alkali metal hydride base and carbonyldiimidazole to formulate

(B) obtaining a compound of

The compound of step (b) is represented by the formula

Is treated with a diamine, wherein A, B, D and E are as defined above.

(C) obtaining a compound of

Provided is a process for preparing a compound of formula 4 comprising the step of ring-closing the compound of step (c) with dilute inorganic or organic acid, optionally deprotecting, and then separating the compound of interest:

Formula 2

Formula 4

In Chemical Formulas 2 and 4 above,

R, A, B, D and E are as defined above,

R ^c is a hydroxy protecting group in formula (2), and is as defined above in formula (4).

An alternative to the above-mentioned method is that step (c) and step (d)

The compound of step (b) is represented by the formula

Of amines wherein A, B, D and E are as defined above and Y is hydroxy.

Obtaining a compound of (c),

The compound of step (c) was treated with triphenylphosphine and diphenylphosphoryl azide and diethylazodicarboxylate in tetrahydrofuran to give similar compounds with Y ₃ N ₃ and to remove the deprotecting group (D) obtaining a similar compound wherein Y is N ₃ and R ^c is H,

The compound of step (d) is treated with a reducing agent selected from the group consisting of triphenylphosphine-water, hydrogen under catalyst, sodium borohydride and dialkylammonium hydride

(E) obtaining a compound of

The compound of step (e) is closed using dilute inorganic or organic acid, and then replaced by steps (c) to (f), which comprise step (f) to separate the desired compound.

In another embodiment, the present invention provides a compound of formula 4a:

Formula 4a

In Formula 4a above,

R, R ^c , A, B, D and E are as defined above.

A preferred embodiment thereof is a compound of formula 4a wherein R ^c is H and R, A, B, D and E are as defined above.

In another embodiment, the present invention provides a compound of formula

Formula 5

In Formula 5 above,

R, R ^b and R ^c are as defined above.

A preferred embodiment of the compound of formula 5 according to the invention is a compound of formula

In Formula 6 above,

R is as defined above.

Representative compounds of formula (6) in this embodiment include, but are not limited to:

A compound of Formula 6 wherein R is -CH ₂ CH ₂ CH ₃ ;

A compound of formula 6 wherein R is -CH ₂ CH = CH;

A compound of Formula 6 wherein R is -CH ₂ CH = CH-phenyl;

A compound of Formula 6 wherein R is -CH ₂ CH ₂ CH ₂ -phenyl;

A compound of Formula 6 wherein R is -CH ₂ CH = NOH;

A compound of Formula 6 wherein R is -CH ₂ CH ₂ NH ₂ ;

A compound of Formula 6 wherein R is -CH ₂ CH ₂ NHCH ₂ -phenyl;

A compound of formula 6 wherein R is -CH ₂ CH ₂ NHCH _2- (4-pyridyl);

A compound of Formula 6 wherein R is -CH ₂ CH ₂ NHCH _2- (4-quinolyl);

A compound of Formula 6 wherein R is -CH ₂ CH (OH) CN;

A compound of Formula 6 wherein R is -CH ₂ CH ₂ NHCH (CO ₂ CH ₃ ) CH ₂ -phenyl;

A compound of Formula 6 wherein R is -CH ₂ CN;

A compound of Formula 6 wherein R is -CH ₂ CH = CH- (4-methoxyphenyl);

A compound of Formula 6 wherein R is -CH ₂ CH = CH- (4-chlorophenyl);

A compound of Formula 6 wherein R is -CH ₂ CH = CH- (4-fluorophenyl);

A compound of formula 6 wherein R is -CH ₂ CH = CH- (3-quinolyl);

A compound of formula 6 wherein R is -CH ₂ CH = CH- (8-quinolyl); and

R is _{-CH 2 CH 2 NHCH 2 CH 2} - A compound of formula (6) (2-chlorophenyl).

In another aspect, the present invention

Chemical formula

Of a compound wherein R ^c is a hydroxy protecting group and R is as defined above

  (1) treating the phosgene reagent selected from phosgene, diphosgene, and triphosgene and alkali metal hydride under anhydrous conditions followed by aqueous base catalyzed decarboxylation; and

(2) reacting with methanesulfonic anhydride in pyridine and then treating with a reagent combination selected from the process with amine bases to obtain a compound of formula 5 wherein R ^b is hydroxy (a),

Optionally, the compound of formula 5 in step (b) wherein R ^b is hydroxy is treated with an alkali metal hydride base and carbonyldiimidazole to yield a compound of formula 5 wherein R ^b is -OC (O) -imidazolyl. Obtaining (b),

Optionally, R ^b is -OC (O) - the imidazole treatment of the compound of formula (5) in the drowsy step (a) with an amine, R ^b is -OC (O) -NH ₂ to obtain a compound of formula 5 (c) and

Provided is a process for preparing a compound of formula 5 comprising the step (d) of optionally deprotecting and then separating the desired compound:

Formula 5

In Formula 5 above,

R and R ^c are as defined above,

R ^b is selected from the group consisting of hydroxy, -OC (O) -NH ₂ and -OC (O) -imidazolyl.

Justice

As used throughout this specification and claims, the following terms have the specific meanings as follows.

As used herein, the terms “C ₁ -C ₃ -alkyl”, “C ₁ -C ₆ -alkyl” and “C ₁ -C ₁₂ -alkyl” each represent one to three, one to six and one to one. It refers to a saturated straight or branched chain hydrocarbon radical derived by the removal of a single hydrogen atom from a hydrocarbon moiety containing 12 carbon atoms. Examples of C ₁ -C ₃ -alkyl radicals are methyl, ethyl, propyl and isopropyl; examples of C ₁ -C ₆ -alkyl radicals are methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, Neopentyl and n-hexyl, but are not limited thereto. Examples of C ₁ -C ₁₂ -alkyl radicals include, but are not limited to, all of the preceding examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.

The term “C ₁ -C ₆ -alkoxy” as used herein refers to a C ₁ -C ₆ -alkyl group as defined above, attached to the parent molecular moiety through an oxygen atom. Examples of C ₁ -C ₆ -alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.

The term “C ₁ -C ₁₂ -alkenyl” refers to a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon moiety having one or more carbon-carbon double bonds and containing 2 to 12 carbon atoms. Examples of alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term “C ₁ -C ₁₂ -alkynyl” as used herein refers to a monovalent group derived by the removal of a single hydrogen atom from a hydrocarbon having one or more carbon-carbon triple bonds and containing 2 to 12 carbon atoms. Refers to. Representative examples of alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl, and the like.

The term "alkylene" means a divalent group derived by the removal of two hydrogen atoms from a straight or branched chain saturated hydrocarbon, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3 -Propylene, 2,2-dimethylpropylene, and the like.

As used herein, the term “C ₁ -C ₃ -alkylamino” refers to one or two C ₁ -C ₃ -alkyl groups as defined above, attached to the parent molecular moiety through a nitrogen atom. . Examples of C ₁ -C ₃ -alkylamino include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino and propylamino.

The term "oxo" refers to a group in which two hydrogen atoms on a single carbon atom in an alkyl group as defined above have been replaced with a single oxygen atom (ie a carbonyl group).

As used herein, the term “aprotic solvent” refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton-donor. Examples thereof include hydrocarbons such as hexane and toluene; Halogenated hydrocarbons such as methylene chloride, ethylene chloride and chloroform; Heteroaryl compounds such as tetrahydrofuran and N-methylpyrrolidinone; And ethers such as diethyl ether, bis-methoxymethyl ether, and the like. Such compounds are well known to those skilled in the art and those skilled in the art will appreciate that individual solvents or mixtures thereof may be specific, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the desired temperature range. And will be preferable to the reaction conditions. Further discussion of aprotic solvents can be found in organic chemistry textbooks and technical books, such as, for example, Organic Solvents Physical Properties and Methods of Purification , 4th ed., Edited by John A. Riddick et al., Vol. II, the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings, examples of which are phenyl, naphthyl, tetrahydronaphthyl, indanyl, Indenyl, and the like, but is not limited thereto. Aryl groups (including bicyclic aryl groups) are unsubstituted or lower alkyl, substituted lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, It may be substituted with one, two or three substituents independently selected from halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "C ₃ -C ₁₂ -cycloalkyl" means a monovalent group derived by the removal of a single hydrogen atom from a monocyclic or bicyclic saturated carbocyclic ring compound. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl and bicyclo [2.2.2] octyl.

As used herein, "halo" and "halogen" refer to atoms selected from fluorine, chlorine, bromine and iodine.

The term "alkylamino" refers to a group having the structure -NHR 'where R' is alkyl as defined above. Examples of alkylamino include methylamino, ethylamino, iso-propylamino and the like.

The term "dialkylamino" refers to a group having the structure -NR'R ", wherein R 'and R" are independently selected from alkyl as defined above. In addition, R ′ and R ″ may together be optionally — (CH ₂ ) _k —, where k is an integer from 2 to 6. Examples of dialkylamino include dimethylamino, diethylaminocarbonyl , Methylethylamino, piperidino and the like.

The term "haloalkyl" refers to an alkyl group as defined above, to which one, two or three halogen atoms are attached, examples of which include chloromethyl, bromoethyl, trifluoromethyl and the like.

The term "alkoxycarbonyl" refers to an ester group, ie an alkoxy group, attached to the parent molecular moiety through a carbonyl group, examples of which include methoxycarbonyl, ethoxycarbonyl and the like.

The term "thioalkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through a sulfur atom.

The term "carboxaldehyde" as used herein, refers to a group of the formula -CHO.

The term "carboxy" as used herein, refers to a group of the formula -CO ₂ H.

As used herein, the term "carboxamide" refers to a group of the formula -CONHR'R "wherein R 'and R" are independently selected from hydrogen and alkyl, or R' and R "together, optionally-( CH ₂ ) _k −, where k is an integer from 2 to 6;

The term “heteroaryl” as used herein, wherein one ring atom is selected from S, O and N; One or two ring atoms is an additional hetero atom independently selected from S, O and N; It refers to cyclic aromatic radicals having 5 to 10 ring atoms, in which the remaining ring atoms are carbon and are connected to the rest of the molecule through any ring atom, examples of which are pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl , Imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxdiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl and the like.

As used herein, the term “heterocycloalkyl” includes bi- or tri-cyclic which may comprise an aromatic 6-membered aryl or heteroaryl ring that contains a single ring of 3 to 8 atoms and is fused to a non-aromatic ring. It refers to a nonaromatic partially unsaturated or fully saturated three to ten member ring system, including a ring system. These heterocycloalkyl rings include those having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatoms can be optionally quaternized.

Examples of representative heterocycles include pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxoxazolidinyl, morpholinyl, thia Zolidinyl, isothiazolidinyl, and tetrahydrofuryl.

Particular heterocycloalkyl rings that are considered useful for preparing the compounds of the present invention include the following: 3-methyl-4- (3-methylphenyl) piperazine, 3-methylpiperidine, 4- (bis -(4-fluorophenyl) methyl) piperazine, 4- (diphenylmethyl) piperazine, 4- (ethoxycarbonyl) piperazine, 4- (ethoxycarbonylmethyl) piperazine, 4- (phenyl Methyl) piperazine, 4- (1-phenylmethyl) piperazine, 4- (1,1-dimethylethoxycarbonyl) piperazine, 4- (2- (bis- (2-propenyl) amino) ethyl) Piperazine, 4- (2- (diethylamino) ethyl) piperazine, 4- (2-clopophenyl) piperazine, 4- (2-cyanophenyl) piperazine, 4- (2-ethoxyphenyl Piperazine, 4- (2-ethylphenyl) piperazine, 4- (2-fluorophenyl) piperazine, 4- (2-hydroxyethyl) piperazine, 4- (2-methoxyethyl) piperazine , 4- (2-methoxyphenyl) piperazine, 4- (2-methylphenyl) piperazine, 4- (2-methylthiophenyl) piperazine, 4- (2-nitrophenyl) piperazine, 4- (2 - Trophenyl) piperazine, 4- (2-phenylethyl) piperazine, 4- (2-pyridyl) piperazine, 4- (2-pyrimidinyl) piperazine, 4- (2,3-dimethylphenyl) Piperazine, 4- (2,4-difluorophenyl) piperazine, 4- (2,4-dimethoxyphenyl) piperazine, 4- (2,4-dimethylphenyl) piperazine, 4- (2, 5-dimethylphenyl) piperazine, 4- (2,6-dimethylphenyl) piperazine, 4- (3-chlorophenyl) piperazine, 4- (3-methylphenyl) piperazine, 4- (3-trifluoro Methylphenyl) piperazine, 4- (3,4-dichlorophenyl) piperazine, 4- (3,4-dimethoxyphenyl) piperazine, 4- (3,4-dimethylphenyl) piperazine, 4- (3, 4-methylenedioxyphenyl) piperazine, 4- (3,4,5-trimethoxyphenyl) piperazine, 4- (3,5-dichlorophenyl) piperazine, 4- (3,5-dimethoxyphenyl Piperazine, 4- (4- (phenylmethoxy) phenyl) piperazine, 4- (4- (1,1-dimethylethyl) phenylmethyl) piperazine, 4- (4-chloro-3-trifluoro Methylphenyl) piperazine, 4- (4-chlorophenyl) -3-methylpiperazine, 4- (4-chlorophenyl) piperazine, 4- (4-chlorophenyl) piperazine, 4- (4-chlorophenylmethyl) piperazine, 4- (4-fluorophenyl) piperazine, 4- (4-methoxyphenyl) piperazine, 4- (4- Methylphenyl) piperazine, 4- (4-nitrophenyl) piperazine, 4- (4-trifluoromethylphenyl) piperazine, 4-cyclohexylpiperazine, 4-ethylpiperazine, 4-hydroxy-4- (4-chlorophenyl) methylpiperazine, 4-hydroxy-4-phenylpiperidine, 4-hydroxypyrrolidine, 4-methylpiperazine, 4-phenylpiperazine, 4-piperidinylpiperazine, 4-((2-furanyl) carbonyl) piperazine, 4-((1,3-dioxolan-5-yl) methyl) piperazine, 6-fluoro-1,2,3,4-tetrahydro 2-methylquinoline, 1,4-diazacycloheptane, 2,3-dihydroindolyl, 3,3-dimethylpiperidine, 4,4-ethylenedioxypiperidine, 1,2,3, 4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, azacyclooctane, decahydroquinoline, piperazine, piperidine, pyrrolidine, thiomor Lin and triazole.

As used herein, the term “heteroarylalkyl” refers to a heteroaryl group, as defined above, attached to the parent molecular moiety through an alkylene group, wherein the alkylene group represents 1 to 4 carbon atoms. Have

The term "hydroxy-protecting group" as used herein refers to an easily removable group known to be able to protect and selectively remove hydroxyl groups from undesirable reactions during the course of the synthesis. The use of hydroxyl protecting groups to protect groups from undesirable reactions during the synthesis process is well known in the art and many such protecting groups are described, for example, in TH Greene and PGM Wuts, Protective Groups. in Organic Synthesis , 2nd edition, John Wiley & Sons, New York (1991). Examples of hydroxy protecting groups include, but are not limited to, ethers such as methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and acetyl benzoyl and the like.

The term “ketone protecting group” as used herein refers to an easily removable group known to be capable of protecting and selectively removing ketone groups from undesirable reactions during the course of the synthesis. The use of ketone protecting groups to protect groups from undesirable reactions during the synthesis process is well known in the art and many such protecting groups are described, for example, in TH Greene and PGM Wuts, Protective Groups in Organic Synthesis , 2nd edition, John Wiley & Sons, New York (1991). Examples of ketone protecting groups include, but are not limited to, ketal, oxime, O-substituted oximes (eg O-benzyl oxime, O-phenylthiomethyl oxime), 1-isopropoxycyclohexyl oxime, and the like.

The term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups. .

The term “protic organic solvent,” as used herein, refers to a solvent that tends to provide protons such as alcohols such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art and those skilled in the art will appreciate that individual solvents or mixtures thereof may be specific compounds depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the desired temperature range. And will be preferable to the reaction conditions. Further discussion of protic solvents can be found in organic chemistry textbooks or specialized books, for example, Organic Solvents Physical Properties and Methods of Purification , 4th ed., Edited by John A. Riddick et al., Vol. II. , the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

As used herein, the term “substituted aryl” means that one, two or three hydrogen atoms are selected from Cl, Br, F, I, OH, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₆ -alkoxy Independently substituted by aryl substituted C ₁ -C ₆ -alkoxy, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide By aryl group as defined above. In addition, the substituent may be an aryl, heteroaryl, or heterocycloalkyl group. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

As used herein, the term “substituted heteroaryl” means that one, two, or three hydrogen atoms are Cl, Br, F, I, OH, CN, C ₁ -C ₃ -alkyl, C ₁ -C _6- Independently with C ₁ -C ₆ -alkoxy, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide substituted by alkoxy, aryl Substituted by reference to heteroaryl groups as defined above. In addition, the substituent may be an aryl, heteroaryl, or heterocycloalkyl group.

As used herein, the term “substituted heterocycloalkyl” means that one, two or three hydrogen atoms are Cl, Br, F, I, OH, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₆ Alkoxy, aryl substituted C ₁ -C ₆ -alkoxy, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide Refers to a heterocycloalkyl group, as defined above, substituted by: In addition, the substituent may be an aryl, heteroaryl, or heterocycloalkyl group.

Numerous asymmetric centers may be present in the compounds of the present invention. Unless stated otherwise, the invention encompasses various stereoisomers and mixtures thereof. Thus, even when the bonds are indicated by dashed lines, there may be individual isomers or mixtures of steric orientations of the indicated or unspecified orientation.

As used herein, the term "pharmaceutically acceptable salt" is suitable and reasonable for use in contact with human and lower animal tissues without causing harmful toxicity, irritation, allergic reactions, etc. under thorough medical judgment. A risk ratio refers to a balanced salt. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in S.M. Berge et al., J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. Such salts may be prepared in situ during the final separation and purification of the compounds of the present invention, or may be prepared separately by reacting the free base functionality with a suitable organic acid. Examples of pharmaceutically acceptable and non-toxic acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts of amino groups formed or formed using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepro Cypionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- Hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, Oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, peak And the like sites, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. In some instances, additional pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. There is an amine cation formed using.

As used herein, the term "pharmaceutically acceptable ester" refers to an ester that is hydrolyzed in vivo and includes readily ruptured in the human body to release the parent compound or salt thereof. Suitable ester groups include, for example, pharmaceutically acceptable aliphatic carboxylic acids, in particular alkanic acid, alkenic acid, cycloalkanoic acid and alkanedioic acid, wherein each alkyl or alkenyl moiety is advantageously 6 or less. Has a carbon atom of Examples of specific esters are formate, acetate, propionate, butyrate, acrylate and ethyl succinate.

As used herein, the term "pharmaceutically acceptable prodrug" is suitable and reasonable for use in contact with tissues of humans and lower animals without causing harmful toxicity, irritation, allergic reactions, etc. under thorough medical judgment. It refers not only to prodrugs of the compounds of the present invention, which are balanced at a risk / risk ratio and effective for the intended purpose, but also to the zwitterionic forms of the compounds of the present invention where possible. The term “prodrug” refers to a compound that is rapidly converted in vivo, for example by hydrolysis in blood, to produce the parent compound of the above formula. A thorough discussion of this can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems , Vol. 14, thd ACS Symposium Series, and Edward B. Roche, ed., Bioreversible Carriers in Drug Design , American Pharmaceutical Association and Pergamon Press, 1987.

Antimicrobial activity

Representative compounds of the present invention were analyzed in vitro for antimicrobial activity as follows: Test compound mixed with 10 ml of sterile Brain Heart Infusion (BHI) agar (Difco 0418-01-5) Twelve Petri dishes containing successive aqueous dilutions of were prepared. Using the Steers replicator block, 1 plate for slow growing strains such as 1: 100 (or Micrococcus and Streptococcus) of up to 32 different microorganisms on each plate. 10) Inoculate the dilution. The plates so inoculated are incubated at 35-37 ° C. for 20-24 hours. In addition, a control plate is prepared using BHI agar containing no test compound and incubated at the beginning and end of each test.

Additional plates containing compounds with the known sensitivity pattern for the organisms tested and belonging to the same antibiotic class as the test compound are also prepared and cultured for test versus test comparisons as well as additional controls. Erythromycin A was used for this purpose.

After incubation, each plate is visually inspected. Minimum Inhibitory Concentration (MIC) is defined as the lowest concentration of drug that shows no, slight cloudiness, or sparse isolated colonies that show growth on inoculum spots as compared to the growth control. These assay results presented in the following Tables 1a to 1v demonstrate the antimicrobial activity of the compounds according to the invention.

Pharmaceutical composition

Pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention formulated with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means any type of nontoxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starches such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; Talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols such as propylene glycol; Esters such as ethyl oleate and ethyl laurate; Agar; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffers as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; In addition, colorants, release agents, coatings, sweeteners, flavoring and flavorings, preservatives and antioxidants may be present in the composition at the discretion of the formulator. The pharmaceutical composition of the present invention is administered to humans and other animals as oral, rectal, parenteral, subretinal alveolar, intravaginal, intraperitoneal, topical (by powder, ointment or drop), intranasal, or oral or nasal spray can do.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solvents, suspensions, syrups and elixirs. Such liquid dosage forms, in addition to the active compounds, are inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germinated oil, olive oil, castor oil, and sesame oil), glycerol, tetra Fatty acid esters of hydrofurfuryl alcohol, polyethylene glycol and sorbitan, and mixtures thereof. The oral composition may include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents, in addition to inert diluents.

Suitable dispersing or wetting agents and suspending agents can be used to formulate injectable preparations, for example, sterile injectable aqueous or oily suspensions, according to techniques known in the art. Such sterile injectable preparations may also be present as sterile injectable solutions, suspensions or emulsions, eg, in 1,3-butanediol, in a nontoxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include water, Ringer's solution, U.S.P. And isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose, all non-irritating nonvolatile oils can be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare the injectable preparations.

Injectable formulations may be sterilized, for example, by filtration with a bacterial retention filter or by incorporation of the sterilant in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use. You can.

In order to prolong drug effects, it is often desirable to slow the absorption of drugs from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials with low water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delay in absorption of the parenterally administered drug type is achieved by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

Compositions for rectal or vaginal administration may be prepared by dissolving the compound of the invention in a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or in the rectum or vagina because it is solid at ambient temperature but liquid at body temperature. Preference is given to suppositories which can be prepared by mixing with the releasing suppository wax.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is prepared by one or more pharmaceutically acceptable inert excipients or carriers, for example sodium citrate or dicalcium phosphate and / or a) starch, lactose, sucrose, glucose, mannitol and salicylic acid. Fillers or extenders such as b) carboxymethyl cellulose, alginate, gelatin, binders such as polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerol, d) agar-agar, calcium carbonate, potato or tapioca Disintegrants such as starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) kaolin and Absorbents such as bentonite and i) talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate The mixture of the lubricant, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise a buffer.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain a milky agent and may also be a composition which releases the active ingredient (s) in only a specific part of the intestine or preferentially in such part, in an optionally delayed manner. Examples of sealing compositions that can be used include polymeric substances and waxes.

Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

The active compound may also be in micro-encapsulated form with one or more excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared using coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with one or more inert diluents, such as sucrose, lactose or starch. Such dosage forms may include additional materials other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as in conventional practice. In the case of capsules, tablets and pills, such dosage forms may comprise buffering agents. They may optionally contain a milky agent and may also be a composition which releases the active ingredient (s) in only a specific part of the intestine or preferentially in such part, in an optionally delayed manner. Examples of sealing compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound according to the invention include ointments, pastes, creams, lotions, gels, powders, solvents, sprays, inhalants or patches. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and, if desired, a preservative or buffer. Ophthalmic formulations, ear drops and the like are considered to be within the scope of the present invention.

Ointments, pastes, creams and gels, in addition to the active compounds of the present invention, include animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxides. Excipients, and mixtures thereof.

The powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. The syrup may additionally contain conventional propellants, such as chlorofluorohydrocarbons.

Transdermal patches have the added advantage of delivering certain compounds to the body in a controlled manner. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the entry of the compound into the skin. The rate of absorption can be controlled by providing an absorption rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

According to the method of treatment of the present invention, a bacterial infection in said patient is treated or prevented by administering a therapeutically effective amount of a compound of the present invention to a patient, such as a human or lower animal, for a time necessary to achieve the desired result. By "therapeutically effective amount" of a compound of the present invention is meant an amount sufficient to treat a bacterial infection of the compound at a reasonable benefit / risk ratio applicable to all medical treatments. However, it should be appreciated that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician in accordance with thorough medical judgment. Specific therapeutically effective amounts for a particular patient can include the disease and the severity of the condition being treated; The activity of the specific compound employed; The specific compound employed; The age, body weight, general health, sex and diet of the patient; Time of administration, route of administration, and rate of secretion of the specific compound employed; Duration of treatment; Drugs used in combination or administered in combination with the specific compound employed; And other factors well known in the medical arts.

The total daily dose of a compound according to the invention administered to a human or other mammal in a single dose or divided into several doses is, for example, 0.01 to 50 mg / kg body weight, more typically 0.1 to 25 mg /. Weight kg. A single dose of the composition may contain this amount or may be divided into several portions to achieve this daily dose. In general, the therapeutic regimen according to the present invention comprises administering from about 10 mg to about 2000 mg of a compound of the present invention in a daily or divided dose to a patient in need thereof.

Abbreviation

The abbreviations used to describe the following schemes and examples are as follows: azobisisobutyronitrile-AIBN; Tributyltin hydride-Bu ₃ SnH; Carbonyldiimidazole-CDI; 1,8-diazabicyclo [5.4.0] undec-7-ene-DBU; Diethylazodicarboxylate-DEAD; Dimethylformamide-DMF; Dimethyl sulfoxide-DMSO; Diphenylphosphoryl azide-DPPA; Triethylamine-Et ₃ N; Ethyl acetate-EtOAc; Diethyl ether-Et ₂ O; Ethanol-EtOH; Acetic acid-HOAc; Methanol-MeOH; Sodium bis (trimethylsilyl) amide-NaN (TMS) ₂ ; N-methylmorpholine N-oxide-NMMO; Triethylamine-TEA; Tetrahydrofuran-THF; And triphenylphosphine-TPP.

Synthesis

The compounds and methods of the present invention will be better understood in conjunction with the following synthetic schemes 1-6 illustrating the preparation of the compounds of the present invention. Compounds of the present invention are prepared by the representative methods described below. Groups A, B, D, E, W, X, Y, Z, R ^a , R ^b , R ^c and R ^d are as defined above unless stated otherwise.

The process for preparing the compound of formula 8 according to the invention from erythromycin A is summarized in Schemes 1a and 1b. The preparation of protected erythromycin A is described in US Pat. Nos. 4,990,602, 4,331,803, 4,680,368 and 4,670,549, which are incorporated herein by reference. European Patent Application No. 260,938 is also incorporated by reference. In general, the C-9-carbonyl group of compound 1 is an oxime, wherein V is = NOR ³ or = NOC (R ⁸ ) (R ⁹ ) -OR ³ , wherein R ³ is as defined above and R ⁸ and R ⁹ is (a) hydrogen, (b) unsubstituted C ₁ -C ₁₂ -alkyl, (c) C ₁ -C ₁₂ -alkyl substituted with aryl and (d) C ₁ -C substituted with substituted aryl _Or R ⁸ and R ⁹ together with the carbon to which they are attached form a C ₃ -C ₁₂ -cycloalkyl ring). Particularly preferred carbonyl protecting group V is O- (1-isopropoxycyclohexyl) oxime.

The 2′- and 4 ″ -hydroxy groups of Compound 2 are described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 2nd ed., John Wiley & Sons, Inc., 1991. The hydroxy protecting group is, for example, acetic anhydride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane or tri, in an aprotic solvent. Alkylsilyl chloride Examples of aprotic solvents include dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone, dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, mixtures thereof, or one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acete Mixtures of nitrite, acetone, etc. The aprotic solvent does not adversely affect the reaction, and dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or mixtures thereof are preferred. The protection of the 2'- and 4 "-hydroxy groups of is performed sequentially or simultaneously to afford compound 3, wherein R ^p is a hydroxy protecting group. Preferred protecting group R ^p is trimethylsilyl.

 The 6-hydroxy group of compound 3 is then alkylated by reacting with an alkylating agent in the presence of a base to yield compound 4. Alkylating agents include alkyl chlorides, bromides, iodides or alkyl sulfonates. Specific examples of alkylating agents include allyl bromide, propargyl bromide, benzyl bromide, 2-fluoroethyl bromide, 4-nitrobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, α-bromo-p-toluni Tril, cinnamil bromide, methyl 4-bromocrotonate, crotyl bromide, 1-bromo-2-pentene, 3-bromo-1-propenyl phenyl sulfone, 3-bromo-1-trimethylsilyl-1 -Propyne, 3-bromo-2-octyne, 1-bromo-2-butyne, 2-picolinyl chloride, 3-picolinyl chloride, 4-picolinyl chloride, 4-bromomethyl quinoline, bromoaceto Nitrile, epichlorohydrin, bromofluoromethane, bromonitromethane, methyl bromoacetate, methoxymethyl chloride, bromoacetamide, 2-bromoacetophenone, 1-bromo-2-butanone, Bromo chloromethane, bromomethyl phenyl sulfone, 1,3-dibromo-1-pro And the like. Examples of alkyl sulfonates are allyl O-tosylate, 3-phenylpropyl-O-trifluoromethane sulfonate, n-butyl-O-methanesulfonate and the like. Examples of solvents used are dimethylsulfoxide, diethylsulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, their Aprotic solvents such as mixtures or mixtures of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, acetone and the like. Examples of bases that may be used include potassium hydroxide, cesium hydroxide, tetraalkylammonium hydroxide, sodium hydride, potassium hydride, potassium isopropoxide, potassium tert-butoxide, potassium isobutoxide and the like.

Deprotection of 2'- and 4 "-hydroxy groups is then described, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 2nd ed., John Wiley & Sons, Inc., 1991. The conversion is typically performed to = N-OH using the conditions used to deprotect the 2'- and 4 "-hydroxy groups. For example, acetonitrile and acetic acid in water can be used to deprotect the 2'- and 4 "-hydroxy groups and X is = NOR ³ or = NOC (R ⁸ ) (R ⁹ ) -OR ³ (where R ³ R ⁸ and R ⁹ are as defined above), and = N-OH.) If this is not the case, the conversion is carried out in a separate step.

The deoxime reaction can be carried out according to the method described in Greene, supra. Examples of the deoxidizing agent include inorganic sulfur oxides such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate and potassium metabisulfite Compound. Examples of solvents used are protic solvents such as water, methanol, ethanol, propanol, isopropanol, trimethylsilanol or one or more mixtures of these solvents. The deoxime reaction is more conveniently carried out in the presence of organic acids such as formic acid, acetic acid and trifluoroacetic acid. The amount of acid used is from about 1 to about 10 equivalents of the amount of compound 5 used. In a preferred embodiment, the deoxime reaction is carried out using an organic acid such as formic acid in ethanol and water to give the desired product 6.

The conversion of 6-substituted erythromycin derivatives to 6-substituted ketolides is described in Scheme 1b. The cladinose residue of macrolide 6 is removed by gentle aqueous acid hydrolysis or by enzymatic hydrolysis to yield compound 7. Representative acids include dilute hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid or trifluoroacetic acid. Suitable solvents for the reaction include methanol, ethanol, isopropanol, butanol and the like. The reaction time is typically 0.5 to 24 hours. The reaction temperature is preferably -10 to 35 ° C. The 2'-hydroxy group of compound 7 is subjected to an aprotic solvent as defined above, preferably dichloromethane, chloroform, DMF, tetrahydrofuran (THF), N-methyl pyrrolidinone or acetic anhydride, benzoyl Protection is by using a suitable hydroxy protection reagent such as anhydride, benzyl chloroformate or trialkylsilyl chloride. Particularly preferred protecting group R ^p is benzoate. It is also possible to reverse the order of removing the clidinos and removing the hydroxy groups without affecting the yield of the process.

The 3-hydroxy group of compound 8 is oxidized to ketone 9 using a modified Swern oxidation process. Suitable oxidizing agents are N-chlorosuccinimide-dimethyl sulfide or carbodiimide-dimethylsulfoxide. In a typical example, compound 8 is added to preformed N-chlorosuccinimide and dimethyl sulfide complex in a chlorinated solvent such as methylene chloride at -10 to 25 ° C. After stirring for 0.5-4 hours, a tertiary amine such as triethylamine or Hunig base is added to produce the corresponding ketone. The 2'-hydroxy protecting group of compound 9 is then removed by standard methods to afford the desired ketolide 8. When R ^p is an ester such as acetate or benzoate, the compound can be deprotected by treatment with methanol or ethanol. When R ^p is a trialkylsilyl group, the compound can be deprotected by treatment with fluoride in THF or acetonitrile.

Compound 8 (where X is O) is then reacted with hydroxylamine hydrochloride in the presence of a base, or with hydroxylamine in the presence of an acid as described in US Pat. No. 5,274,085 to give R ¹ H. An oxime derivative can be manufactured by forming a phosphorus compound. When reacted with substituted hydroxylamine R ¹ ONH ₂ , a compound in which R ¹ is not H is formed. Alternatively, compounds wherein R ¹ is not H may initially form unsubstituted oximes as mentioned above and then react with R ¹ X ′ where X ′ is a suitable leaving group such as halogen. It can manufacture.

The preparation of compounds of formula 9 according to the invention, wherein L is CO and T is -NH- or -N (WR ^d )-, is summarized in Schemes 1c and 4. According to Scheme 1c, 6-O-substituted Compound 6 is first protected by a suitable hydroxy protecting group by the procedure referred to above to give Compound 6A. Compound 6A is then treated with sodium hexamethyldisilazide and carbonyldiimidazole to yield compound 6B. In particular, treatment of compound 6B with aqueous ammonia results in the formation of cyclic carbamate 6C with R ^e as H. Likewise, reacting compound 6B with a compound of formula H ₂ NWR ^d forms a cyclic carbamate wherein R ^e is -WR ^d .

Alternative or additional processes can be used to prepare compounds of formula 9, wherein L is CO and T is -N (WR ^d )-. For example, compound 6C, wherein R ^e is H, is treated with an alkylating agent of the formula R ^d -halogen, where R ^d is as defined above to give compound 6C, where R ^e is WR ^d and W is not present. R ^d is as defined above].

Reaction of compound 6B with a hydrazine compound of formula H ₂ N-NH-R ^d results in the formation of a cyclic carbamate, which yields compound 6C wherein R ^e is WR ^d , W is -NH- and R ^d is as defined above. ] Is obtained. If unsubstituted hydrazine is the reagent, the final product is compound 6C, wherein R ^e is —N (WR ^d ) —wherein (WR ^d ) is (NH ₂ ).

Compound 6C, wherein R ^e is —N (WR ^d ) —wherein (WR ^d ) is (NH ₂ )] is treated with an alkylating agent of the formula R ^d -halogen, wherein R ^d is as defined above; 6C, wherein R ^e is WR ^d , W is —NH— and R ^d is as defined above.

Compound 6C was treated with an acylating agent selected from the group consisting of R ^d -C (CO) -halogen and (R ^d -C (CO) -O) ₂ , where R ^e is W, W is -NH-CO- and R ^d affords compound 6C as defined above.

Compound 6C, wherein R ^e is —N (WR ^d ) —wherein (WR ^d ) is (NH ₂ ), is treated with aldehyde R ^d —CHO, wherein R ^d is as defined above, where W is — Yields Compound 6C where N = CH- and R ^d is as defined above.

A compound of formula 9 wherein L is CO and T is -N (WR ^d )-wherein (WR ^d ) is (NH ₂ ) is a alkylating agent of the formula R ^d -halogen, wherein R ^d is as defined above ] Yields a compound of formula 9 wherein L is CO and T is -N (WR ^d )-and W is absent and R ^d is as defined above.

Reacting compound 6B with a hydroxylamine compound of formula H ₂ NOR ^d forms a cyclic carbamate wherein R ^e is -OR ^d .

The cladinose residues are removed by acid hydrolysis as mentioned above to give compound 6D wherein Z 'is H. Compound 6D is then oxidized to Compound 6E by the modified Swen oxidation process described for Scheme 1b above to convert Compound 8 to ketone 9.

Deprotection of the 2'-hydroxy group as mentioned above yields the desired ketolide VII.

According to another procedure set forth in Scheme 1d, compound 2A, the 9-oxime compound of erythromycin A, was subjected to acid hydrolysis with an inorganic acid or an organic acid as mentioned above to remove the cladanose residue and to yield compound 7A. do. Oxime compound 7B protected by reacting oxime compound 7A with an appropriately substituted oxime protection reagent, wherein V is = NOR ¹ (as shown) or = NOC (R ⁵ ) (R ⁶ ) -OR ¹ (where R ¹ , R ⁵ and R ⁶ are as defined above). The 3 and 2'-hydroxy groups of compound 7B are protected as mentioned above, preferably using trimethylsilyl protecting groups to give compound 7C. Subsequently, compound 7C is alkylated as mentioned for Scheme 1a to yield compound 7D, which compound 1D is first deoxygenated as described for Scheme 1a, and the product so deoxyxed is shown in Scheme 1c. Conversion to compound 7E is as described for preparing compound 6C from 6A. Subsequently, the compound 7E was deprotected and the above-mentioned process proceeded to the 3-ketolide derivative compound of formula 9, wherein X is O and L is CO and T is -NH- or -N (WR ^d )-. Oxidize.

Compounds of formula 9 according to the invention, wherein L is CO and T is O, and a process for the preparation of compounds of formula 6 are shown in Scheme 2. In Scheme 2, the manufacturing process is described in Baker et al., J. Org. Chem., 1988, 53, 2340. In particular, the 2 'protected ketolide derivative 9 prepared as described in Scheme 1 above is converted to cyclic carbonate 10 by reacting with carbonyldiimidazole and sodium hexamethyldisilazide. Deprotection as mentioned above yields compound 9, wherein L is CO and T is O.

The compound of formula 6 is prepared from compound 9 by reacting with sodium hydride or lithium hydride and phosgene, diphosgene or triphosgene under anhydrous conditions and then aqueous post-treatment (aqueous base catalyzed decarboxylation). Alternatively, compound 9 is converted to its corresponding mesylate by reaction with methanesulfonic anhydride in pyridine. The mesylate is then converted to compound 11 by treatment with an amine base such as DBU or dimethylaminopyridine in acetone or acetonitrile. The 2 'protecting group is removed as mentioned above to afford compound VI.

In addition, the compound of formula 6 is substituted with an amine base such as 1,8-diazocyclo [5.5.0] undec-7-ene (DBU) or 4-dimethylaminopyridine (DMAP) in a solvent such as benzene or acetonitrile. By treating or reacting with sodium hydride or lithium hydride in tetrahydrofuran or N, N-dimethylformamide (DMF) to afford compound 11, and then deprotection as mentioned above to give the desired compound. Prepared from 10.

Compounds of formula 7 are prepared as described in Schemes 3a and 3b. According to Scheme 3a, ketolide 11 prepared in Scheme 2 is reacted with an alkali metal hydride base such as sodium hydride, lithium hydride or potassium hydride and carbonyldiimidazole in a suitable aprotic solvent at about 0 ° C. to ambient temperature. Convert to compound 12. Compound 12 may also be prepared by reacting diol 9, or cyclic carbonate 10 prepared as described in Scheme 2, above with carbonyldiimidazole and sodium or lithium hydride under similar conditions. Compound 12 is then reacted with diamine 13 with substituents A, B, D and E as defined above in a suitable solvent such as aqueous acetonitrile, DMF or aqueous DMF to afford bicyclic compound 14. Compound 14 is then closed by treatment with dilute acid such as acetic acid or HCl in a suitable organic solvent such as ethanol or propanol and then deprotected as mentioned above to give tricyclic ketolide VII. Alternatively, the 2'-protecting group of bicyclic ketolide 14 can be removed prior to ring closure using the method described in Scheme 1. The compound of formula 4 or VII may be reduced to the compound of formula 4a by treatment with a reducing agent selected from hydrogen, alkyl borohydride and lithium aluminum hydride in the presence of a palladium catalyst in a suitable organic solvent.

Scheme 3b illustrates another method for preparing the compound of formula 7. Starting material 12 was reacted with beta-aminoalcohol 15 (Y = OH) in a suitable solvent system such as aqueous acetonitrile, DMF or aqueous DMF at 0-70 ° C. to give compound 16, which was then subjected to trihydrofuran Conversion to azide is performed using a Mitsunobu reaction using phenylphosphine and diphenylphosphoryl azide and DEAD. Alternatively, the hydroxy group in compound 16 can be activated by treatment with sulfonyl chloride, alkyl or aryl sulfonic anhydride or trifluoromethanesulfonic anhydride in an aprotic solvent. This activated hydroxy group is converted to the corresponding azide by reaction with lithium azide or sodium azide in an aprotic solvent. The 2'-protecting group is then removed as mentioned above and the azide is reduced to amine 17. Suitable reducing agents are triphenylphosphine-water, catalysts and hydrogen, sodium borohydride or dialkylaluminum hydride in solvents suitable for these reactions, as is well known in the art. Compound 17 is then ring closed as described in Scheme 3a above.

A compound of formula 9 is prepared as shown in Scheme 4, wherein L is CO and T is NH or NWR ^d . Such methods are described in Baker et al., J. Org. Chem., 1988, 53, 2340. In particular, treatment of compound 12 prepared as described in Scheme 3 with aqueous ammonia results in the formation of cyclic carbamate 18, wherein R ^e is H. Likewise, reacting Compound 12 with an amino compound of Formula H ₂ NWR ^d results in the formation of a cyclic carbamate wherein R ^e is -WR ^d .

As mentioned above, the 2'-hydroxy group is deprotected to provide the desired ketolide VII. In particular, treatment of compound 6B with aqueous ammonia results in the formation of cyclic carbamate 6C with R ^e as H. Likewise, reacting compound 6B with an amino compound of formula H ₂ NWR ^d forms a cyclic carbamate wherein R ^e is -WR ^d .

The desired 6-O-substituted compounds can be obtained directly as mentioned above or by chemically modifying the initially prepared 6-O-substituted compounds. Representative examples of further modifications at the 6-position are shown in Scheme 5. For example, it is further possible to derive compound 20 wherein R is 6-O-CH ₂ CH = CH ₂ and M 'represents a macrolide ring system. (A) catalytically reducing the double bond of the allyl compound to yield 6-O-propyl compound 27; (b) treatment with osmium tetraoxide to give 2,3-dihydroxypropyl compound 31, which is functionalized at each oxygen atom such as esterification with an acylating agent such as acyl halide or acyl anhydride to give compound 32 Can be obtained; (c) oxidation with m-chloroperoxybenzoic acid in an aprotic solvent to afford epoxy methyl compound 29, which is ring-opened using a nucleophilic compound, such as an amine or an N-containing heteroaryl compound, to N To obtain compound 30 having a containing side chain; (d) references; 6-O-CH ₂ -C (O) -CH ₃ Compound 28 oxidized under Backer conditions as described in Henry, "Palladium Catalyzed Oxidation of Hydrocarbons", Reidel Publishing Co., Dordrecht, Holland (1980). To obtain; (e) ozonation to give aldehyde 21, which is converted to oxime 22 and 24 by (1) reacting with H ₂ NOR ³ or H ₂ NOH, respectively, or (2) a suitable amine in the presence of a borohydride reducing agent. Amine 23 can be obtained by reductive amination or by forming an imine followed by catalytic reduction, such as using. Oxime 24 is reacted with diisopropyl carbodiimide in an aprotic solvent in the presence of CuCl to give nitrile 25. Compound 20 was subjected to Heck conditions [Pd (II) or Pd (O), phosphine, and an amine or inorganic base; Compound 26 is obtained by reaction with an aryl halide under Organic Reactions, 1982, 27, 345-390. The double bond in compound 26 is reduced using, for example, H ₂ and palladium on carbon, to yield compound 33.

Scheme 6 illustrates another procedure for preparing a compound of Formula 11 wherein L is CO, T is -NH- or -NWR ^d -and R is substituted alkenyl. 6-O-allyl erythromycin Compound 33 is L and is CO and T is -NH- or -N (WR ^d )-by cladinose removal and oxidation of 3-hydroxy groups as described in the previous scheme. Is converted to the compound of formula 11 wherein R is allyl. Subsequently, a compound of formula 11 wherein L is CO, T is -NH- or -N (WR ^d )-and R is allyl is subjected to heck conditions [Pd (II) or Pd (O), phosphine, and amine or inorganic base; Under Organic Reactions, 1982, 27, 345-390, reacted with a compound of the formula R ^** -halogen, wherein R ^** is aryl, substituted aryl, heteroaryl or substituted heteroaryl; This is CO, T is N (R ^d ) and R is substituted alkenyl to give the desired product of formula (11).

Alternatively, compound 33 may be substituted with an aryl halide, substituted aryl halide, heteroaryl halide or substituted under heck conditions [Pd (II) or Pd (O), phosphine, and an amine or inorganic base as described above). Reaction with heteroaryl halide converts to 6-O- (substituted alkenyl) compound of formula 34. Subsequently, compound 34 was obtained by removing dino, and oxidizing 3-hydroxy groups, as described in the previous scheme, wherein L is CO and T is -NH- or -N (WR ^d )-and R is substituted. Can be converted to the desired product of formula (11).

Representative examples of further modifications at the 6-position are shown in Scheme 7. The desired 6-O-substituted compound can be prepared by chemically modifying the initially prepared 6-O-propargyl compound. For example, compound 35 can be further derived wherein R is 6-O-CH ₂ -C≡CH and M 'represents a macrolide ring system. Triple bonds of alkyne compounds 35 to aryl halides, substituted aryl halides, heteroaryl halides or substituted heteroaryl halides in the presence of Pd (triphenylphosphine) ₂ Cl ₂ and CuI in the presence of organic amines such as triethylamine Treatment can yield compound 36. Compound 35 was also treated with boronic acid derivative HB (OR ^zz ), wherein R ^zz is H or C ₁ -C ₁₀ -alkyl, in an aprotic solvent at 0 ° C. to ambient temperature to yield compound 37 This is treated with Pd (triphenylphosphine) ₄ and an aryl halide, substituted aryl halide, heteroaryl halide or substituted heteroaryl halide under Suzuki reaction conditions to give compound 38. Compound 35 can also be treated with N-halosuccinimide in acetic acid to yield compound 39. Compound 35 is also formulated with Ar-CH = CH-halogen where Ar is aryl, substituted aryl, heteroaryl in the presence of Pd (triphenylphosphine) ₂ Cl ₂ and CuI in the presence of organic amines such as triethylamine. Or substituted heteroaryl] to provide an appropriately substituted compound 41. In addition, compound 36 can be selectively reduced to the corresponding cis-olefin compound 40 by catalytic hydrogenation in ethanol under atmospheric pressure in the presence of 5% Pd / BaSO ₄ and quinoline. Rao et al., J Org. Chem., 1986, 51: 4158-4159.

Scheme 8 illustrates another process for preparing compounds of Formula 11 wherein L is CO, T is -NH- or -N (WR ^d )-and R is substituted alkynyl. 6-O- propargyl erythromycin compound 42 a, as described in scheme of the prior cladinosyl's removed and the 3-hydroxy by oxidation of the hydroxy group L is CO and T is N (R ^d) and R is a profile gilin Can be converted to a compound of formula (11). Subsequently, the compound of formula 11 wherein L is CO, T is N (R ^d ) and R is propargyl is added in the presence of Pd (triphenylphosphine) ₂ Cl ₂ and CuI in the presence of an organic amine such as triethylamine. Is reacted with a compound of the formula R ^** -halogen, where R ^** is aryl, substituted aryl, heteroaryl or substituted heteroaryl, where L is CO and T is -NH- or N (WR ^d )- Obtain the desired product of Formula 11 wherein R is substituted alkynyl.

Compound 42 is a compound of formula R ^** -halogen wherein R ^** is aryl in the presence of Pd (triphenylphosphine) ₂ Cl ₂ and CuI in the presence of an organic amine such as triethylamine, as described above. , Substituted aryl, heteroaryl or substituted heteroaryl] to a 6-O- (substituted alkynyl) compound of formula 43. Subsequently, compound 43 was subjected to alky, wherein L is CO and T is -NH- or -N (WR ^d )-and R is substituted by cladinos removal and oxidation of the 3-hydroxy group as described in the previous scheme. Is converted to the desired product of formula (11).

Example

The foregoing description is provided by way of illustration of the invention and is not intended to limit the scope of the inventive concept, but may be better understood by reference to the following examples.

Example 1

A compound of formula 8; X is O and R is allyl

Step 1a: Compound 4 from Scheme 1a; V is NO- (1-isopropoxycyclohexyl), R is allyl and R ^p is trimethylsilyl

2 ', 4 "-bis-O-trimethylsilylerythromycin A 9- [O- (1-isopropoxycyclohexyl] oxime (1.032 g) in 5 ml of DMSO and 5 ml of THF, prepared according to the method of US Pat. No. 4,990,602. Freshly distilled allyl bromide (0.73 ml, 2.00 mmol) was added to a 0 ° C. solution of 1.00 mmol) After about 5 minutes, potassium tert-butoxide solution (1 M 2.0 ml, 2.0 ml in 5 ml of DMSO and 5 ml of THF). ml) is added dropwise over 4 hours The reaction mixture is dissolved in ethyl acetate and washed with water and brine The organic phase is concentrated in vacuo to afford the desired compound (1.062 g) as a white foam.

Step 1b: Compound 5 from Scheme 1a; V is NOH and R is allyl

To a solution of compound (1.7 g) from step 1a in 17 ml of acetonitrile and 8.5 ml of water is added 9 ml of acetic acid at ambient temperature. After several hours at ambient temperature, the reaction mixture is diluted with 200 ml of toluene and then concentrated in vacuo. Since the obtained residue was found to contain unreacted starting material, additional acetonitrile (15 ml), water (70 ml) and HOAc (2 ml) were added. After 2 hours, an additional 1 ml aliquot of HOAc is added. After approximately three hours or more, the reaction mixture is placed in the freezer overnight. The reaction mixture is warmed to ambient temperature, diluted with 200 ml of toluene and concentrated in vacuo. The residue is chased twice with toluene and dried to constant weight (1.524 g).

Step 1c: Compound 6 from Scheme 1a; R is allyl

Compound (1.225 g) resulting from step 1b in 16 ml 1: 1 ethanol: water was treated with NaHSO ₃ (700 mg) and formic acid (141 μL) and warmed at 86 ° C. for 2.5 h. The reaction mixture is cooled to ambient temperature, diluted with 5-6 ml of water, basified with 1N NaOH to pH 9-10 and extracted with ethyl acetate. The combined organic extracts are washed with brine (twice), dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was purified by column chromatography eluting with 1% MeOH in methylene chloride containing 1% ammonium hydroxide to give 686 mg (57%) of the title compound.

¹³ C NMR (CDCl ₃ ) δ 219.3 (C-9), 174.8 (C-1), 135.5 (C-17), 116.3 (C-18), 101.9 (C-1 '), 95.9 (C-1 "), 79.7 (C-5), 78.8 (C-6), 78.5 (C-3), 74-1 (C-12), 72.4 (C-3"), 70.6 (C-11), 68.1 ( C-5 '), 65.5 (C-16), 65.1 (C-2'), 49.0 (C-3 "O-CH ₃ ), 45.0 (C-2), 44.1 (C-8), 39.7 (NMe ₂ ), 37.9 (C-4), 37.1 (C-10), 34.6 (C-2 "), 28.4 (C-4 '), 21.0, 20.6 (C-3" CH ₃ , C-6' CH ₃ ), 20.8 (C-14), 18.3 (C-6 "), 18.1 (C-8 CH ₃ ), 15.7, 15.6 (C-2 CH ₃ , C-6 CH ₃ ), 11.9 (C-10 CH ₃ ), 10.1 (C-15), 8.9 (C-4 CH ₃ ). MS (FAB) + m / e 774 (M + H) ⁺ , 812 (M + K) ⁺ .

Step 1d: Compound 7 from Scheme 1b; R is allyl

To a suspension of the compound prepared in step 1c (7.73 g, 10.0 mmol) in ethanol (25 ml) and water (75 ml) was added aqueous 1M HCl (18 ml) over 10 minutes. The reaction mixture is stirred at ambient temperature for 9 hours and then left overnight in the freezer. Aqueous 2M NaOH (9 ml, 18 mmol) forms a white precipitate. The mixture is diluted with water and then filtered. The solid is washed with water and dried under vacuum to afford descladinosyl compound 7 (3.11 g).

Step 1e: Compound 8 from Scheme 1b; R is allyl and R ^p Is benzoyl

To a solution of the product of step 1d (2.49 g, 4.05 mmol) in dichloromethane (20 ml) was added benzoic anhydride (98%, 1.46 g, 6.48 mmol) and triethylamine (0.90 ml, 6.48 mmol) and the white suspension was brought to ambient temperature. Stir for 26 h. Aqueous 5% sodium carbonate is added and the mixture is stirred for 20 minutes. The mixture is extracted with dichloromethane. The organic phase is washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (2.46 g) as a white solid.

Step 1f: Compound 9 from Scheme 1b; R is allyl and R ^p Is benzoyl;

R ^a Is OH and R ^c Is the same as the compound of formula 2 wherein is benzoyl

Dimethylsulfide (0.43 ml, 5.92 mmol) was added over 5 minutes to a -10 ° C. solution of N-chlorosuccinimide (0.68 g, 5.07 mmol) in dichloromethane (20 ml) under N ₂ . The resulting white slurry was stirred at −10 ° C. for 20 minutes, then a solution of compound (2.43 g, 3.38 mmol) from step 1e in dichloromethane (20 ml) was added and the reaction mixture was stirred at −10 to −5 ° C. at 30 ° C. Stir for minutes. Triethylamine (0.47 ml, 3.38 mmol) is added dropwise over 5 minutes and the reaction mixture is stirred at 0 ° C. for 30 minutes. The reaction mixture is extracted with dichloromethane. The organic phase is washed twice with aqueous 5% sodium bicarbonate, then once with brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (2.27 g) as a white foam.

Step 1g: Compound of Formula 8; X is O and R is allyl

The solution of compound (719 mg, 1.0 mmol) from step 1f in methanol (20 ml) is stirred under reflux for 6 hours. The reaction mixture is concentrated in vacuo and the residue is chromatographed on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) to afford the desired compound (577 mg) as a white foam.

¹³ C NMR (CDCl ₃ ) δ219.2 (C-9), 206.0 (C-3), 169.8 (C-1), 135.3, 117.5, 102.8, 78.4, 78.0, 75.9, 74.4, 70.3, 69.5, 69.0, 65.9, 64.6, 50.6, 45.4, 45.1, 40.2, 38.6, 37.8, 31.6, 28.4, 21.8, 21.3, 20.3, 18.1, 16.5, 14.7, 12.8, 12.3, 10.6. MS (FAB) + m / e 614 (M + H) ⁺ .

Example 2

A compound of formula 8; X is NOH and R is allyl

To a solution of the compound (122 mg, 0.2 mmol) from Example 1 in ethanol are added hydroxylamine hydrochloride (76 mg, 1.1 mmol) and triethylamine (56 μl, 0.4 mmol) and the reaction mixture is stirred at 80 ° C. overnight. . The reaction mixture is concentrated and the residue is dissolved in ethyl acetate. The organic phase is washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords E oxime (42 mg) and Z oxime (38 mg) as white foams.

¹³ C NMR (CDCl ₃ ) δ 206.3 (C-3), 170.1 (C-9), 169.8 (C-1), 136.1, 116.5, 102.7, 78.6, 78.2, 75.5, 74.1, 70.3, 70.2, 69.4, 65.9, 64.7, 50.6, 45.2, 40.2, 37.3, 33.1, 28.4, 25.4, 21.9, 21.3, 20.3, 18.6, 16.5, 14.9, 14.7, 12.8, 10.7 MS (FAB) + m / e 629 (M + H) ⁺ .

Example 3

A compound of formula 8; X is O and R is propyl

A solution of compound (122 mg, 0.2 mmol) from Example 1 in ethanol is flushed under nitrogen and 10% palladium on carbon (20 mg) is added. The mixture is then flushed with hydrogen and the reaction mixture is stirred overnight under positive hydrogen pressure. The reaction mixture is filtered and concentrated in vacuo to give a glass. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound as a white solid.

¹³ C NMR (CDCl ₃ ) δ220.2 (C-9), 206.5 (C-3), 169.9 (C-1), 102.7, 78.1, 77.7, 75.7, 74.1, 70.3, 69.4, 65.9, 64.5, 50.6, 45.4, 44.7, 40.2, 38.8, 37.5, 28.4, 22.3, 21.9, 21.3, 20.3, 18.3, 16.5, 14.9, 14.7, 12.4, 10.6, 10.2. MS (FAB) + m / e 616 (M + H) ⁺ .

Example 4

A compound of formula 8; X is O and R is -CH ₂ CHO

Step 4a: a compound of Formula 8; X is O and R is -CH ₂ CHO N-oxide

Ozone is passed through a -78 ° C solution of the compound (2.45 g, 4.0 mmol) resulting from Example 1 in dichloromethane (100 ml) for 45 minutes. The reaction mixture is then flushed with nitrogen for 10 minutes. Dimethyl sulfide (1.46 ml, 20 mmol) is added at -78 ° C and the reaction mixture is stirred at 0 ° C for 30 minutes. The reaction mixture is concentrated in vacuo to give a white foam (2.78 g) which is used without further purification.

Step 4b: compound of Formula 8; X is O and R is -CH ₂ CHO

The desired compound is prepared by heating the compound obtained from step 4a (2.78 g, 4.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in THF (40 ml) at 55 ° C. for 2.5 hours. The reaction mixture is concentrated in vacuo to give a white foam. Chromatography on silica gel (1: 1 acetone-hexane, then 75: 25: 0.5 acetone-hexane-triethylamine) affords the desired compound (1.29 g) as a white solid. MS (FAB) + m / e 616 (M + H) ⁺ .

Example 5

A compound of formula 8; X is O and R is -CH ₂ CH = NOH

To a solution of compound (46 mg, 0.08 mmol) prepared in Example 4 in methanol (5 ml) was added triethylamine (31 μl, 0.225 mmol) and hydroxylamine hydrochloride (7.7 mg, 0.112 mmol) and the reaction mixture was Stir at temperature for 6 hours. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a clear glass. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound (29 mg) as a white solid. MS (FAB) + m / e 631 (M + H) ⁺ .

Example 6

A compound of formula 8; X is NOH and R is -CH ₂ CH = NOH

The title compound (7.0 mg) is obtained from the chromatography described in Example 5. MS (FAB) ⁺ m / e 631 (M + H) ⁺ . MS (FAB) ⁺ m / e 645 (M + H) ⁺ .

Example 7

A compound of formula 8; X is O and R is -CH ₂ CN

 To a nitrogen solution of compound (168 mg, 0.267 mmol) prepared in Example 5 in THF (5 ml) was added diisopropylcarbodiimide (83 μl, 0.534 mmol) and CuCl (2.7 mg, 0.027 mmol) and the reaction mixture was Stir overnight at ambient temperature. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a clear glass. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound (63 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ219.5 (C-9), 205.6 (C-3), 169.9 (C-1), 103.4, 81.3, 78.2, 77.4, 77.1, 74.0, 70.2, 69.7, 69.1, 65.9, 51.1, 48.6, 46.7, 44.3, 40.2, 38.0, 37.6, 28.2, 23.5, 21.2, 19.7, 17.8, 16.1, 14.4, 11.9, 10.5, 10.5. MS (FAB) + m / e 613 (M + H) ⁺ .

Example 8

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NH ₂ to be

To a solution of the compound (170 mg, 0.276 mmol) prepared in Example 4 in methanol (10 ml) was added ammonium acetate (212 mg, 2.76 mmol) and the mixture was cooled to 0 ° C. Sodium cyanoborohydride (34 mg, 0.553 mmol) is added and the reaction mixture is stirred at 0 ° C. for 30 h. The reaction mixture is dissolved in ethyl acetate and washed with aqueous 5% sodium bicarbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (90: 10: 0.5 dichloromethane-methanol-ammonia) affords the title compound (90 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ217.0 (C-9), 206.3 (C-3), 170.6 (C-1), 102.7, 78.9, 75.1, 74.9, 70.3, 69.4, 67.8, 65.9, 63.1, 50.8, 45.8, 44.9, 41.7, 40.3, 38.8, 38.2, 28.4, 22.2, 21.3, 20.7, 19.2, 16.6, 14.9, 12.8, 12.4, 10.9. MS (FAB) + m / e 617 (M + H) ⁺ .

Example 9

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NHCH ₂ -Phenyl

To a 0 ° C. solution of the compound (121.3 mg, 0.200 mmol) prepared in Example 4 in methanol (10 ml) was added acetic acid (114 μl, 2.00 mmol) and benzylamine (218 μl, 2.00 mmol) and the mixture was stirred for 10 minutes. do. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) is added and the reaction mixture is stirred for 16 hours. Additional sodium cyanoborohydride (24.8 mg, 0.400 mmol) is added and stirring is continued for 5 hours. The reaction mixture is dissolved in ethyl acetate and washed with aqueous 5% sodium bicarbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) followed by second chromatography (50: 50: 0.5 acetone-hexane-triethylamine) afforded the title compound (82 mg) as a white foam. do.

¹³ C NMR (CDCl ₃ ) δ 216.6 (C-9), 206.3 (C-3), 170.5 (C-1), 139.0, 128.6, 128.3, 126.9, 102.4, 78.9, 78.4, 75.1, 74.8, 70.2, 69.4, 67.8, 65.9, 61.7, 53.2, 50.7, 48.2, 45.6, 44.8, 40.2, 38.8, 38.0, 28.3, 21.9, 21.3, 20.6, 18.8, 16.6, 14.6, 12.6, 12.3, 10.7. MS (FAB) + m / e 707 (M + H) ⁺ .

Example 10

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ -Phenyl

To a 0 ° C. solution of the compound (121.3 mg, 0.200 mmol) prepared in Example 4 in methanol (10 ml) was added acetic acid (114 μl, 2.00 mmol) and phenethylamine (218 μl, 2.00 mmol) and the mixture was stirred for 10 minutes. Stir. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) is added and the reaction mixture is stirred for 16 hours. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium carbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (90: 10: 0.5 dichloromethane-methanol-ammonia) affords the title compound (60.1 mg) as a white foam. MS (FAB) + m / e 721 (M + H) ⁺ .

Example 11

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NHCH (CO ₂ CH ₃ ) CH ₂ -Phenyl

To a 0 ° C. solution of the compound (121.3 mg, 0.200 mmol) prepared in Example 4 in methanol (10 ml) was added L-phenylalanine methyl ester hydrochloride (129 mg, 0.600 mmol) and the mixture was stirred for 10 minutes. Sodium cyanoborohydride (24.8 mg, 0.400 mmol) is added and the reaction mixture is stirred for 22 hours. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium carbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound (60.1 mg) as a white foam.

¹³ C NMR (CDCl ₃ ) δ 217.8 (C-9), 206.4 (C-3), 170.5 (C-1), 170.4, 137.5, 129.4, 128.2, 126.4, 102.4, 78.8, 78.4, 75.2, 74.9, 70.2, 69.4, 68.5, 65.9, 63.1, 61.6, 51.4, 50.7, 47.1, 45.5, 44.7, 40.2, 39.2, 38.4, 28.4, 21.8, 21.2, 20.6, 18.7, 16.6, 14.7, 12.6, 12.2, 10.7. MS (FAB) + m / e 779 (M + H) ⁺ .

Example 12

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NHCH ₂ -(4-pyridyl)

Except for replacing phenethylamine with 4-aminomethylpyridine, the target compound is obtained according to the method of Example 10.

¹³ C NMR (CDCl ₃ ) δ217.8 (C-9), 206.2 (C-3), 170.6 (C-1), 149.7, 148.2, 123.3, 102.5, 78.9, 78.4, 75.0, 74.9, 70.2, 69.5, 68.4, 65.9, 61.7, 52.4, 50.7, 48.7, 45.7, 44.8, 40.2, 39.2, 38.5, 38.2, 28.4, 21.8, 21.3, 20.6, 18.7, 16.6, 14.6, 12.6, 12.2, 10.7. MS (FAB) + m / e 708 (M + H) ⁺ .

Example 13

A compound of formula 8; X is O and R is -CH ₂ CH ₂ NHCH ₂ -(4-quinolyl)

In a solution of the compound (90 mg, 0.15 mmol) prepared in Example 8 in methanol (2 ml), 4-quinolinecarbaldehyde (23 mg, 0.15 mmol), acetic acid (8.6 μl, 0.15 mmol) and sodium cyanoborohydride ( 9.4 mg, 0.15 mmol) is added and the reaction mixture is stirred for 15 hours. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium carbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (90: 10: 0.5 dichloromethane-methanol-ammonia) affords the title compound (32 mg) as off-white solid. MS (FAB) + m / e 758 (M + H) ⁺ .

Example 14

A compound of formula 8; X is O and R is -CH ₂ CH = CH-phenyl

Step 14a: Compound 9 from Scheme 2; X is O, R is -CH ₂ CH = CH-phenyl and R ^p is benzoyl

In a nitrogen solution of acetonitrile (5 ml), the compound prepared in Example 1, Step 6 (717 mg, 1.00 mmol), palladium (II) acetate (22 mg, 0.100 mmol) and triphenylphosphine (52 mg, 0.200 mmol) Iodobenzene (220 μl, 2.00 mmol) and triethylamine (280 μl, 2.00 mmol) are added and the mixture is cooled to −78 ° C., degassed and sealed. The reaction mixture is then warmed to 60 ° C. for 0.5 h and stirred at 80 ° C. for 12 h. The reaction mixture is dissolved in ethyl acetate and washed twice with aqueous 5% sodium bicarbonate, once with aqueous 2% tris (hydroxymethyl) aminomethane, then once with brine, dried over sodium sulfate, After filtration, it is concentrated in vacuo. Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound (721 mg) as off-white foam.

Step 14b: compound of Formula 8; X is O and R is -CH ₂ CH = CH-phenyl

The compound prepared in Example 14a is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 219.4 (C-9), 206.0 (C-3), 169.8 (C-1), 137.0, 132.6, 128.3, 127.3, 126.7, 126.6, 102.7, 78.4, 78.2, 75.9, 74.3, 70.3, 69.5, 69.1, 65.9, 64.2, 50.6, 45.4, 45.3, 40.2, 38.7, 37.7, 28.3, 21.9, 21.2, 20.3, 18.1, 16.5, 14.6, 13.0, 12.3, 10.8. MS (FAB) + m / e 690 (M + H) ⁺ .

Example 15

A compound of formula 8; X is O and R is -CH ₂ CH ₂ CH ₂ -Phenyl

A solution of the compound (170 mg, 0.247 mmol) prepared in Example 14 in methanol (10 ml) is flushed with nitrogen. 10% palladium on carbon (50 mg) is added and the mixture is flushed with hydrogen and stirred under positive hydrogen pressure for 18 hours. The reaction mixture is filtered through celite and the filter cake is washed with dichloromethane. The filtrate is concentrated in vacuo to give a colorless glass. This glass is dissolved in ether, hexanes are added and the solvent is removed in vacuo to yield the title compound (67 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ220.2 (C-9), 206.5 (C-3), 170.0 (C-1), 142.3, 128.4, 128.1, 125.4, 102.6, 78.2, 78.0, 75.6, 74.2, 70.3, 69.5, 69.4, 65.9, 62.1, 50.6. 45.4, 44.6, 40.2, 38.8, 37.5, 32.1, 30.3, 28.4, 21.9, 21.3, 20.2, 18.4, 16.5, 14.9, 12.4, 10.6. MS (FAB) + m / e 692 (M + H) ⁺ .

Example 16

A compound of formula 8; X is O and R is -CH ₂ CH = CH- (4-methoxyphenyl)

The desired compound is prepared according to the method of Example 14, except that iodobenzene is replaced with 4-iodoanisole. MS (FAB) + m / e 720 (M + H) ⁺ .

Example 17

A compound of formula 8; X is O and R is -CH ₂ CH = CH- (4-chlorophenyl)

The desired compound was prepared according to the method of Example 14 except for replacing iodobenzene with 1-chloro-4-iodobenzene.

¹³ C NMR (CDCl ₃ ) δ219.6 (C-9), 206.0 (C-3), 169.8 (C-1), 139.6, 135.5, 131.3, 128.5, 127.9, 127.3, 102.7, 78.4, 78.2, 75.9, 74.2, 70.3, 69.5, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2, 38.6, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0, 12.2, 10.8. MS (FAB) + m / e 724 (M + H) ⁺ .

Example 18

A compound of formula 8; X is O and R is -CH ₂ CH = CH- (3-quinolyl)

Step 18a: Compound 9 from Scheme 2; X is O, R is -CH ₂ CH = CH- (3-quinolyl ) and R ^p is benzoyl

Example 1, compound prepared in step f (1.80 g, 0.25 mmol), palladium (II) acetate (11 mg, 0.05 mmol), tri-o-tolylphosphine (30 mg, 0.10 mmol) in acetonitrile (2 ml) and The mixture of 3-bromoquinoline (68 μl, 0.5 mmol) is cooled to −78 ° C., degassed and then sealed. The reaction mixture is then warmed to 50 ° C. for 2 hours and stirred at 80 ° C. for 16 hours. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium carbonate, aqueous 2% tris (hydroxymethyl) aminomethane and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (98: 2 dichloromethane-methanol) affords the title compound (186 mg) as off-white foam. MS (FAB) + m / e 845 (M + H) ⁺ .

Step 18b: compound of Formula 8; X is O and R is -CH ₂ CH = CH- (3-quinolyl)

The compound prepared in Example 18a is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 219.7 (C-9), 205.9 (C-3), 169.8 (C-1), 152.1, 150.0, 147.5 140.2, 132.6, 130.0, 129.2, 129.1, 128.8, 128.1, 127.9, 126.5, 102.8, 78.5, 78.2, 75.9, 74.2, 70.2, 69.4, 69.2, 65.9, 64.1, 50.6, 45.4, 45.3, 40.2, 38.7, 37.6, 28.4, 21.8, 21.2, 20.3, 18.0, 16.5, 14.6, 13.0, 12.2, 10.8.

MS (FAB) + m / e 741 (M + H) ⁺ .

Using the procedures described in the previous examples and schemes and using methods known in the field of synthetic organic chemistry, the compounds of formula 8 wherein X is O can be prepared. Compounds having R substituents as described in the following table are as follows:

Example 71

A compound of formula 9; L is CO, T is O and R is -CH ₂ CH = CH ₂ to be

Step 71a: Compound 10 from Scheme 2; R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

To a -35 ° C. solution of compound (3.58 g, 5.00 mmol) prepared in Example 1, step f in THF (60 ml) was added sodium hexamethyldisilazide (1.0 M in THF, 5.5 ml, 5.5 mmol) The resulting white suspension is stirred for 30 minutes. A solution of carbonyldiimidazole (4.05 g, 25 mmol) in THF (40 ml) was added dropwise at −35 ° C. over 20 minutes, the cold bath was removed and the reaction mixture was stirred for 30 minutes. The reaction mixture is dissolved in ethyl acetate, washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulphate, filtered and concentrated in vacuo. Chromatography on silica gel (30% acetone-hexane) affords the title compound (2.6 g) as a white foam. MS (FAB) + m / e 744 (M + H) ⁺ .

Step 71b: compound of Formula 9; L is CO, T is O and R is -CH ₂ CH = CH ₂ to be

The compound prepared in Example 71a is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 212.1 (C-9), 205.0 (C-3), 168.9 (C-1), 153.8, 134.4, 118.4, 103.1, 84.7, 80.5, 78.7, 77.1, 76.9, 70.3, 69.5 , 65.9, 64.8, 50.8, 46.5, 44.1, 40.2, 38.8, 38.1, 28.4, 22.7, 21.2, 20.5, 18.3, 14.5, 13.6, 12.6, 10.6.

MS (FAB) + m / e 640 (M + H) ⁺ .

Example 72

A compound of formula 9; L is CO, T is O and R is -CH ₂ CH = CH-phenyl

Step 72a: Compound 10 from Scheme 2; R is -CH ₂ CH = CH-phenyl and R ^p Is benzoyl

The solution of compound (150 mg, 0.20 mmol) prepared in Example 14, step a in THF (5 ml) is cooled to −35 ° C. and flushed with nitrogen. Lithium hexamethyldisilazide (1.0 M in THF, 0.22 ml, 0.22 mmol) was added at -35 ° C. over 2 minutes. The reaction mixture is stirred at −35 ° C. for 10 minutes, then a solution of carbonyldiimidazole (162 mg, 1.00 mmol) in THF (3 ml) is added dropwise over 2 minutes. The cold bath is removed and the reaction mixture is stirred for 30 minutes. The reaction mixture is cooled to 0 ° C. and 0.5M aqueous KH ₂ PO ₄ is added. The mixture is extracted with ethyl acetate and the organic phase is washed with brine, dried over sodium sulfate and then concentrated in vacuo. Chromatography on silica gel (30% acetone-hexane) affords the title compound (87 mg) as a white solid. MS (FAB) + m / e 820 (M + H) ⁺ .

Step 72b: compound of Formula 9; L is CO, T is O and R is -CH ₂ CH = CH-phenyl

The compound prepared in Example 72a is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 212.4 (C-9), 205.2 (C-3), 168.3 (C-1), 153.3, 136.4, 134.9, 128.3, 127.6, 127.0, 124.7, 103.2, 84.5, 80.8, 78.7 , 78.0, 70.3, 69.6, 65.9, 64.5, 50.9, 46.9, 44.4, 40.2, 39.1, 37.8, 28.3, 23.0, 21.2, 20.4, 18.1, 14.8, 14.4, 13.7, 12.6, 10.8.

MS (FAB) + m / e 716 (M + H) ⁺ .

Example 73

A compound of formula 9; L is CO, T is O and R is -CH ₂ CH ₂ CH ₂ -Phenyl

Step 73a: compound 8 from scheme 1b; R is -CH ₂ CH ₂ CH ₂ -Phenyl and R ^p Is benzoyl

The desired compound is prepared by reacting the compound of Example 15 with benzoic anhydride according to Example 1, step e.

Step 73b: compound 10 from Scheme 1b; R is -CH ₂ CH ₂ CH ₂ -Phenyl and R ^p Is benzoyl

The solution of compound (104 mg, 0.13 mmol) prepared in step 73a in THF (5 ml) is cooled to −35 ° C. and flushed with nitrogen. Sodium hexamethyldisilazide (1.0 M in THF, 0.16 ml, 0.16 mmol) is added at −35 ° C. over 1 minute. The reaction mixture is stirred at −35 ° C. for 10 minutes, then a solution of carbonyldiimidazole (105 mg, 0.65 mmol) in THF (3 ml) is added dropwise over 1 minute. The cold bath is removed and the reaction mixture is stirred for 30 minutes. The mixture is extracted with ethyl acetate and the organic phase is washed with 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a colorless glass. Chromatography on silica gel (30% acetone-hexane) affords the title compound (63 mg) as a white solid. MS (FAB) + m / e 822 (M + H) ⁺ .

Step 73c: a compound of Formula 9; L is CO, T is O and R is -CH ₂ CH ₂ CH ₂ -Phenyl

The compound prepared in Example 73b is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 211.8 (C-9), 205.1 (C-3), 169.6 (C-1), 153.6, 141.9, 128.5, 128.1, 125.5, 102.7, 84.6, 80.5, 78.3, 76.0, 70.2 , 69.5, 65.9, 62.4, 50.7, 45.5, 44.5, 40.2, 38.6, 37.9, 31.9, 30.4, 28.4, 22.6, 21.2, 20.3, 18.5, 14.6, 13.4, 13.3, 12.6, 10.4.

MS (FAB) + m / e 718 (M + H) ⁺ .

Example 74

A compound of formula 9; L is CO, T is O and R is -CH ₂ CH = CH- (4-chlorophenyl)

Step 74a: compound 10 from scheme 1b; R is -CH ₂ CH = CH- (4-chlorophenyl) and R ^p is benzoyl

A solution of the compound of formula 10 prepared in Example 17 (wherein R is -CH ₂ CH = CH- (4-chlorophenyl) and R ^p is benzoyl) (165 mg, 0.20 mmol) in THF (5 ml) Cool to 35 ° C. and flush with nitrogen. Lithium hexamethyldisilazide (1.0 M in THF, 0.22 ml, 0.22 mmol) was added at -35 ° C. over 2 minutes. The reaction mixture is stirred at −35 ° C. for 10 minutes, then a solution of carbonyldiimidazole (105 mg, 0.65 mmol) in THF (3 ml) is added dropwise over 2 minutes. The cold bath is removed and the reaction mixture is stirred for 30 minutes. The mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a colorless glass (219 mg) which is used without further purification. MS (FAB) + m / e 854 (M + H) ⁺ .

Step 74b: compound of Formula 9; L is CO, T is O and R is -CH ₂ CH = CH- (4-chlorophenyl )

The compound prepared in Example 74a is deprotected by heating in methanol according to Example 1, step g.

¹³ C NMR (CDCl ₃ ) δ 212.4 (C-9), 205.1 (C-3), 168.6 (C-1), 153.3, 135.0, 133.5, 133.2, 128.5, 128.3, 125.5, 103.2, 84.5, 80.7, 78.8 , 78.0, 70.3, 69.6, 66.0, 64.3, 50.9, 46.9, 44.4, 40.2, 39.1, 37.8, 28.4, 23.0, 21.2, 20.4, 18.1, 14.8, 14.4, 13.6, 12.6, 10.7.

MS (FAB) + m / e 750 (M + H) ⁺ .

Example 75

A compound of formula 9; L is CO, T is O and R is -CH ₂ CH = CH- (3-quinolyl)

Using the procedure of Example 71, steps a and b, the compound of formula 10 prepared in Example 18 wherein R is -CH ₂ CH = CH- (3-quinolyl) and R ^p is benzoyl) Convert to the title compound.

¹³ C NMR (CDCl ₃ ) δ 212.4 (C-9), 205.2 (C-3), 168.7 (C-1), 153.4, 150.3, 147.6, 132.7, 131.1, 129.6, 129.0, 128.9, 128.4, 128.1, 127.7 , 126.6, 103.2, 84.5, 80.6, 78.9, 77.5, 77.0, 70.3, 69.6, 65.9, 64.3, 50.9, 46.9, 44.5, 40.3, 39.0, 37.8, 28.4, 22.8, 21.2, 20.4, 18.1, 14.7, 14.4, 13.5 , 12.6, 10.6.

MS (FAB) + m / e 767 (M + H) ⁺ .

Using the procedures described in the previous examples and schemes and using methods known in the field of synthetic organic chemistry, the compounds of formula 9 wherein L is CO and T is O can be prepared. Compounds having R substituents as described in the following table are as follows:

Example 102

A compound of formula 9; L is CO, T is NH and R is -CH ₂ CH = CH ₂ to be

Step 102a: Compound 11 from Scheme 2; R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

1,8-dia in a solution of Example 71, compound 10 (where R is -CH ₂ CH = CH ₂ and R ^p is benzoyl) (2.59 g, 3.48 mmol) in benzene (100 ml) Xabicyclo [5.4.0] undec-7-ene (DBU, 5.0 ml, 34 mmol) is added. The reaction mixture is flushed with nitrogen, warmed to 80 ° C. and stirred for 3.5 h. The reaction mixture is cooled to 0 ° C. and 0.5M aqueous NaH ₂ PO ₄ (100 ml) is added. The mixture is extracted twice with ethyl acetate and the combined organic layers are washed with brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (1.74 g) as a white solid. MS (FAB) + m / e 700 (M + H) ⁺ .

Step 102b: Compound 12 from Scheme 3a; R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

The solution of compound (1.74 g, 2.49 mmol) prepared in step 102a in THF (30 ml) is cooled to −10 ° C. and flushed with nitrogen. Sodium hydride (80% in mineral oil, 150 mg, 5.00 mmol) is added and the reaction mixture is stirred for 10 minutes. A solution of carbonyldiimidazole (1.22 g, 7.50 mmol) in THF (20 ml) is added over 10 minutes at -10 ° C. The cold bath is removed and the reaction mixture is stirred for 1 hour. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (1.58 g) as a white solid. MS (FAB) + m / e 794 (M + H) ⁺ .

Step 102c: Compound 18 from Scheme 4; R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

The compound (1.19 g, 1.5 mmol) prepared in step 102b is dissolved in THF (2 ml) and acetonitrile (20 ml) and the solution is flushed with nitrogen. Aqueous ammonium hydroxide (28%, 21 ml) is added and the reaction mixture is stirred for 24 hours under nitrogen. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (0.56 g) as a white solid. MS (FAB) + m / e 743 (M + H) ⁺ .

Step 102d: a compound of Formula 9; L is CO, T is NH and R is -CH ₂ CH = CH ₂ to be

The title compound is prepared by heating in methanol according to Example 1, step g, to deprotect the compound prepared in step 102c.

¹³ C NMR (CDCl ₃ ) δ 216.9 (C-9), 205.3 (C-3), 169.5 (C-1), 158.0, 134.4, 118.2, 102.8, 83.7, 78.4, 77.1, 76.1, 70.2, 69.5, 65.9 , 64.7, 57.8, 50.8, 45.9, 45.1, 40.2, 38.9, 37.3, 28.3, 22.6, 21.2, 20.2, 18.1, 14.5, 13.8, 13.7, 10.6.

MS (FAB) + m / e 639 (M + H) ⁺

Example 103

A compound of formula 9; L is CO, T is NH and R is -CH ₂ CH = CH-phenyl

Replace the compound of Example 1, step f with the compound prepared in Example 102, step c, which is Compound 18 of Scheme 4 wherein R is allyl and R ^p is benzoyl and 3-bromoquinoline is iodobenzene Except for replacing with, the procedure of Example 18 was used to prepare the target compound.

¹³ C NMR (CDCl ₃ ) δ 217.1 (C-9), 205.3 (C-3), 169.5 (C-1), 157.4, 136.5, 133.7, 128.6, 127.8, 126.5, 125.4, 102.9, 83.4, 78.4, 77.7 , 76.4, 70.3, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1, 40.2, 39.1, 37.3, 31.5, 28.3, 22.8, 21.2, 20.3, 18.1, 14.4, 14.2, 13.7, 10.8.

MS (FAB) + m / e 715 (M + H) ⁺

Example 104

A compound of formula 9; L is CO, T is NH and R is -CH ₂ CH = CH- (3-quinolyl)

Example 18, except that the compound of Example 1, step f is replaced with the compound prepared in Example 102, step c, which is Compound 18 of Scheme 4, wherein R is allyl and R ^p is benzoyl. The procedure is used to prepare the desired compound.

¹³ C NMR (CDCl ₃ ) δ 217.4 (C-9), 205.3 (C-3), 169.6 (C-1), 157.7, 149.7, 147.6, 132.5, 129.9, 129.6, 129.2, 129.1, 128.6, 128.1, 126.7 , 102.9, 83.5, 78.8. 77.5, 76.5. 70.2, 69.5, 65.9, 64.3, 58.2, 50.9, 46.3, 45.1, 40.2, 39.1, 37.4, 28.2, 22.6, 21.2, 20.2, 18.1, 14.4, 14.2, 13.7, 10.7.

MS (FAB) + m / e 766 (M + H) ⁺

Using the procedures described in the previous examples and schemes and using methods known in the field of synthetic organic chemistry, the compounds of formula 9 can be prepared wherein L is CO and T is NH. Compounds having R substituents as described in the following table are as follows:

Example 134

A compound of formula 7; A, B, D and E are H and R is allyl

Step 134a: Compound of Formula 14 (Scheme 3a); A, B, D and E are H and R is allyl and R ^p Is benzoyl

Ethylenediamine (291 mg, 4.85 mmol) was added to a solution under nitrogen of acetonitrile compound of formula 12 prepared in Example 102, step b, wherein R is allyl and R ^p is benzoyl; 385 mg, 0.485 mmol The mixture is stirred for 67 hours. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to afford the title compound (401 mg) as a colorless oil which is used without further purification. do.

Step 134b: a compound of Formula 7; A, B, D and E are H and R is allyl

The crude oil prepared in step 134a is dissolved in methanol (5 ml), acetic acid (60 μl) is added and the reaction mixture is stirred at ambient temperature for 15 hours. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a pale yellow glass (347 mg). Chromatography on silica gel (95: 5: 0.5 dichloromethane-methanol-ammonia) affords the title compound (126 mg) as a white foam. MS m / e 664 (M + H) ⁺ .

Using the procedures described in the previous examples and schemes and using methods known in the field of synthetic organic chemistry, the compounds of formula 7 can be prepared wherein A, B, D and E are H. Compounds having R substituents as described in the following table are as follows:

Example 164

A compound of formula 7; A, B and E are H, D is benzyl and R is allyl

Step 164a: 2- (R)-(BOC-amino) -3-phenyl-1-propanol

To a sample of 5.2 g (23.8 mmol) of di-t-butyl dicarbonate in 20 ml of methylene chloride maintained at 0 ° C., (R) -2-amino-3-phenyl-1-propanol (3.0 g, 19.8 mmol, commercially available: Aldrich (Aldrich)) and the reaction mixture is stirred at room temperature for 1.5 hours. The solvent is removed, the residue is dried under high vacuum and used directly in the next step.

Step 164b: 2- (R)-(BOC-amino) -1-O-methanesulfonyloxy-3-phenylpropane

The material from step 164a is dissolved in 20 ml of methylene chloride and 5 ml of THF and the solution is cooled to 0 ° C. Triethylamine (4.1 ml, 29.4 mmol) is added followed by the slow addition of methanesulfonyl chloride (1.9 ml, 24.5 mmol). The mixture is stirred at room temperature for 45 minutes and then the solvent is removed in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with water and brine, dried (Na ₂ SO ₄ ) and filtered. The solvent is removed in vacuo to yield 6.38 g of the title compound. MS m / z (M + H) ⁺ : 330, MS m / z (M + NH ₄ ) ⁺ : 347.

Step 164c: 1-azido-2- (R)-(BOC-amino) -3-phenylpropane

Compound (6.36 g, 193 mmol) from step 164b was dissolved in 25 ml of DMF and 2.5 g (38 mmol) of NaN ₃ were added. The reaction mixture is stirred at 62 ° C. for 24 hours. The solution is cooled to room temperature and then extracted with ethyl acetate. The organic extract is washed with water and brine, dried (Na ₂ SO ₄ ) and filtered. The solvent is removed in vacuo to afford 4.34 g of the title compound. MS m / z (M + H) ⁺ : 277, MS m / z (M + NH ₄ ) ⁺ : 294.

Step 164d: 1-azido-2- (R) -amino-3-phenylpropane

Compound (4.3 g, 15.6 mmol) from step 164c is dissolved in 30 ml of 4N HCl in ethanol and the reaction mixture is stirred at room temperature for 1.5 hours. Strip the solvent and chase with ether. The residue is dissolved in water, NaCl is added and the mixture is extracted with ethyl ether and then decanted. The aqueous layer is adjusted to pH 12 with K ₂ CO ₃ , saturated with NaCl and then extracted with CHCl ₃ . The organic extract is washed with brine, dried (Na ₂ SO ₄ ) and filtered. The solvent is removed in vacuo to afford 2.17 g of the title compound. MS m / z (M + H) ⁺ : 177, MS m / z (M + NH ₄ ) ⁺ : 194.

Step 164e: 1,2- (R) -diamino-3-phenylpropane

Compound samples (1.2 g, 6.8 mmol) from step 164d are hydrogenated (4atm) on ethanol at 1.2 g 10% Pd / C at room temperature in ethanol for 21.5 hours. The mixture is filtered to remove the catalyst and the solvent is removed to give the title compound (1.055 g). MS m / z (M + H) ⁺ : 151, MS m / z (M + NH ₄ ) ⁺ : 168.

Step 164f: compound 14 from scheme 3a; A, B and E are H, D is benzyl, R is allyl and R ^p is benzoyl

In aqueous acetonitrile, the compound prepared as in Example 102, step b (which is compound 12 from Scheme 3a, wherein R is allyl and R ^p is benzoyl) and 1,2 prepared as in step 164e above The desired compound is prepared by stirring a solution of-(R) -diamino-3-phenylpropane for a time sufficient to nearly consume all starting material.

Step 164g: Compound 14 from Scheme 3a; A, B and E are H, D is benzyl, R is allyl and R ^p Is H

The title compound is prepared by heating in methanol according to Example 1, step g, to deprotect the compound prepared in step 164f.

Step 164h: a compound of Formula 7; A, B and E are H, D is benzyl and R is allyl

The desired compound is prepared by heating a solution of the compound prepared in step 164 g in ethanol-acetic acid.

Example 165

A compound of formula 7; A is benzyl, B, D and E are H and R is allyl

Step 165a: Compound 16 from Scheme 3b; A is benzyl, B, D and E are H, Y is OH , R is allyl and R ^p is benzoyl

Replacing 1,2- (R) -diamino-3-phenylpropane with (S) -2-amino-3-phenyl-1-propanol (commercially available from Aldrich Chemical Co.) Except for the preparation of the desired compound according to Example 164, step f.

Step 165b: compound 16 from scheme 3b; A is benzyl, B, D and E are H, Y is N ₃ , R is allyl and R ^p is benzoyl

The desired compound is prepared by treating the solution of the compound of step 165a in THF with triphenylphosphine, diethylazodicarboxylate and diphenylphosphoryl azide.

Step 165c: Compound 16 from Scheme 3b; A is benzyl, B, D and E are H, Y is N ₃ , R is allyl and R ^p is H

The desired compound is prepared by deprotecting the compound prepared in step 165b by heating in methanol according to Example 1, step g.

Step 165d: Compound 17 from Scheme 3b; R is allyl

The desired compound is prepared by refluxing the product of step 165d and a solution of triphenylphosphine in THF.

Step 165e: a compound of Formula 7; A is benzyl, B, D and E are H and R is allyl

The desired compound is prepared by heating the solution of the compound prepared in step 165d in ethanol-acetic acid.

Example 166

A compound of formula 7; A and E are phenyl, B and D are H and R is allyl

Example 164, except that 1,2- (R) -diamino-3-phenylpropane was replaced with 1,2-diphenyl-1,2-ethylenediamine (commercially available from Aldrich Chemical Company), The desired compound is prepared according to the method of step f.

Example 167

A compound of formula 7; A is methyl, B, D and E are H and R is allyl

Except for replacing (S) -2-amino-3-phenyl-1-propanol with (S) -2-amino-1-propanol (commercially available from Aldrich Chemical Company), the method of Example 165 was used. Thus, the desired compound is prepared.

Example 168

A compound of formula 7; A and D are methyl, B and E are H and R is allyl

Step 168a: Meso-2,3-bis (methanesulfonyloxy) butane

Samples of meso-2,3-butanediol (10 g, 111 mmol, commercially available from Aldrich) and triethylamine (92.8 ml, 666 mmol) are dissolved in methylene chloride. The solution is cooled to -78 ° C and methanesulfonyl chloride (25.8 ml, 333 mmol) is added dropwise. A precipitate is formed. The mixture is diluted with additional methylene chloride and the mixture is stirred at −78 ° C. for 20 minutes and then at 0 ° C. for 2 hours. The reaction mixture is allowed to warm to room temperature and diluted with additional solvent and then washed with H ₂ O, aqueous HaHCO ₃ and aqueous NaCl. The organic solution is dried over MgSO ₄ and then the solvent is removed to give the title compound (25.01 g). ¹ H NMR (300 MHz, CDCl ₃ ): δ 4.91 (q, 2H), 3.10 (s, 6H), 1.45 (d, 6H).

Step 168b: Meso-2,3-diazidobutane

A sample of compound (25 g) from step 168a is dissolved in 250 ml of DMF and NaN ₃ (40 g) is added. The mixture is stirred vigorously at 85 ° C. for 24 hours and then cooled to room temperature. The mixture is diluted with 800 ml of ether, then washed with H ₂ O, aqueous HaHCO ₃ and aqueous NaCl, and then dried over MgSO ₄ . The solution is filtered and concentrated to give the title compound (13.00 g). ¹ H NMR (300 MHz, CDCl ₃ ): δ 3.50 (m, 2H), 1.30 (d, 6H),

Step 168c: Meso-2,3-butanediamine

The compound sample (13.0 g, 125 mmol) from step 168b is dissolved in ethanol and hydrogenated at 4 atm on 10% Pd / C for 20 hours at room temperature. The catalyst is filtered off and the solvent is removed in vacuo to afford the title compound. ¹ H NMR (300 MHz, CDCl ₃ ): δ2.70 (m, 2H), 1.45 (br, 4H), 1.05 (d, 6H). MS (m / z): 89 (M + H) ⁺ .

Step 168d: a compound of Formula 7; A and D are methyl, B and E are H and R is allyl

The method of Example 164, steps c through h, except that 1,2- (R) -diamino-3-phenylpropane was replaced with meso-2,3-butanediamine prepared as in step 168c. Thus, the desired compound is prepared.

Example 169

A compound of formula 7; A and E together, -CH ₂ CH ₂ CH ₂ And B and D are H and R is allyl

The desired compound was prepared according to the method of Example 168, except for replacing meso-2,3-butanediol with 1,2-cyclopentane diol (Aldrich Chemical Co., commercially available).

Example 170

A compound of formula 7; A, B, D and E are H and R is -CH ₂ CH = CH- (3-quinolyl)

The desired compound is prepared by coupling the product of Example 134 with 3-bromoquinoline according to the method of Example 18. MS (FAB) + m / e 791 (M + H) ⁺ .

Example 171

A compound of formula 7; A, B, D and E are H and R is -CH ₂ CH ₂ CH ₂ -(3-quinolyl)

To a sample of compound (110 mg) from Example 170 in methanol (10 ml) flushed with nitrogen is added 10% Pd / C (50 mg) and the mixture is stirred at room temperature under 1 atm of hydrogen for 16 hours. The mixture is filtered and concentrated and the residue is purified by chromatography on silica gel eluting with 95: 5: 0.5 to 90: 10: 0.5 dichloromethane / methanol / dimethylamine to afford the title compound (106 mg). High resolution. Elemental analysis for MS m / e (M + H) ⁺ C ₄₄ H ₆₄ N ₄ O ₉ : calcd 793.4752; Found 793.4766.

Example 172

Compound of Formula 8: X is O and R is CH ₂ -(3-iodophenyl)

Except for replacing allyl bromide of step 1f with 3-iodobenzyl bromide, the procedure of Example 1 is followed to prepare the title compound. MS (FAB) + m / e 949 (M + H) ⁺ .

Example 173

Compound of Formula 8: X is O and R is CH ₂ -(2-naphthyl)

The procedure of Example 1 is followed to prepare the title compound, except that the allyl bromide of step 1a is replaced with (2-naphthyl) methyl bromide and the benzoic anhydride in step 1e is replaced with acetic anhydride. MS (FAB) + m / e 714 (M + H) ⁺ ; Elemental analysis for C ₄₀ H ₅₉ NO ₁₀ : Calcd: C, 67.30; H, 8.33; N, 1.96; Found: C, 66.91; H, 8.29; N, 1.64.

Example 174

Compound of Formula 8: X is O and R is CH ₂ -CH = CH- (4-fluorophenyl)

Except for replacing iodobenzene in step 14a with 4-fluoro-1-iodobenzene, the procedure of Example 172 is followed to prepare the title compound.

Example 175

Compound of Formula 8: X is O and R is CH ₂ -CH (OH) -CN

Chromatographic separation from the reaction mixture of the crude product of Example 8 affords the title compound. MS (FAB) + m / e 643 (M + H) ⁺ .

Example 176

Compound of Formula 9: L is CO, T is NH and R is CH ₂ -(2-naphthyl)

Step 176a: Compound 6 from Scheme 1a; R is -CH ₂ -(2-naphthyl)

Except for replacing allyl bromide of step 1a with (2-naphthyl) methyl bromide, the procedure of Example 1, steps a to c is followed to prepare the title compound. MS (FAB) + m / e 874 (M + H) ⁺ .

Step 176b: Compound 6A from Scheme 1c; R is -CH ₂ -(2-naphthyl) and R ^p Is acetyl

Except for replacing the benzoic anhydride of Example 1 with acetic anhydride, the compound from step 176a (2.0 g) is treated according to the procedure of Example 1, step e. MS (FAB) + m / e 958 (M + H) ⁺ .

Step 176c: Compound 6B from Scheme 1c; R is -CH ₂ -(2-naphthyl) and R ^p Is acetyl

Example 102, The compound of step 176b (500 mg) was treated with NaH and carbonyldiimidazole according to the procedure of step b to give the title compound (58 mg). MS (FAB) + m / e 1034 (M + H) ⁺ .

Step 176d: Compound 6C from Scheme 1c; R is -CH ₂ -(2-naphthyl) and R ^p Is acetyl and R ^d Is H

The compound of step 176c (58 mg) was treated with ammonia in acetonitrile according to the procedure of Example 102, step c to afford the title compound. MS (FAB) + m / e 983 (M + H) ⁺ .

Step 176e: a compound of Formula 9; L is CO, T is NH and R is -CH ₂ -(2-naphthyl)

The compound of step 176d is treated following the procedure of Example 1, steps 1d, 1f and 1g to afford the title compound. MS (FAB) + m / e 739 (M + H) ⁺ .

Example 177

Compound of Formula 3: R ^c Is acetyl, L is CO, T is NH and R is -CH ₂ CH = CH ₂ to be

Step 177a: Compound 6A from Scheme 1c; R is -CH ₂ -CH = CH ₂ And R ^p Is acetyl

To dimethylaminopyridine (0.488 g, 4 mmol) and acetic anhydride (3.39 ml, 36 mmol) were added to a sample of the compound from Example 1 step c (405.2 g, 528 mmol) in dichloromethane (20 ml) and the mixture was stirred at room temperature for 3 hours. Stir. The mixture is diluted with methylene chloride and then washed with 5% aqueous sodium bicarbonate and brine and dried over Na ₂ SO ₄ . The residue is dried and recrystallized from acetonitrile to give the title compound (491 g). MS (FAB) + m / e 857 (M + H) ⁺ .

Step 177b: compound 6B from scheme 1c; R is -CH ₂ -CH = CH ₂ And R ^p Is acetyl

To the sample of compound (85.8 g, 100 mmol) from step 177a in anhydrous THF (500 ml) cooled to -40 ° C. and flushed with nitrogen was added sodium bis (trimethylsilyl) amide (125 ml, 125 mmol) over 20 minutes and the mixture was added. Stir at −40 ° C. for 40 minutes. To this mixture is added a solution of carbonyldiimidazole (3.65 g, 22.56 mmol) in 5: 3 THF / DMF (800 ml) under nitrogen at −40 ° C. over 30 minutes and the mixture is stirred at −20 ° C. for 30 minutes. . The mixture is stirred at rt for 27 h and then diluted with ethyl acetate. The mixture is washed with 5% aqueous sodium bicarbonate and brine, dried over Na ₂ S0 ₄ and concentrated to give the title compound (124 g), which is used directly in the next step.

Step 177c: compound 6C from scheme 1c; R is -CH ₂ -CH = CH ₂ , R ^p is acetyl and R ^d is H

Compound (124 g) from step 177b is dissolved in 9: 1 acetonitrile / THF (1100 ml), ammonium hydroxide (28%, 200 ml) is added and the mixture is stirred at room temperature under nitrogen for 8 days. The solvent is removed and the residue is dissolved in ethyl acetate. The solution is washed with 5% aqueous sodium bicarbonate and brine, dried over Na ₂ S0 ₄ and concentrated to afford the title compound. MS (FAB) + m / e 882 (M + H) ⁺ .

Step 177d: compound 6D from scheme 1c; R is -CH ₂ -CH = CH ₂ And R ^p Is acetyl and R ^d Is H

To the sample of compound (69.0 g, 78.2 mmol) from step 177c suspended in ethanol (200 ml) and diluted with water (400 ml) was added dropwise HCl (0.972N, 400 ml) over 20 minutes. The mixture is stirred for 4 hours and additional HCl is added over 20 minutes (4N, 100 ml). The mixture is stirred for 18 hours, cooled to 0 ° C. and then NaOH (4N, 200 ml) is added over 30 minutes to bring the pH to about 9. The title compound is isolated by filtration (35.56 g).

Step 177e: compound 6E from scheme 1c; R is -CH ₂ -CH = CH ₂ And R ^p Is acetyl and R ^d Is H [compound of formula 3; R ^c Is acetyl, L is CO, T is NH and R is -CH ₂ CH = CH ₂ to be]

To a solution of N-chlorosuccinimide (2.37 g, 17.8 mmol) in nitrogen at −10 ° C. in dichloromethane (80 ml) was added dimethylsulfide (1.52 ml, 20.8 mmol) for 5 minutes. The resulting white slurry was stirred at −10 ° C. for 10 minutes, a solution of the compound (8.10 g, 11.9 mmol) from step 177d in dichloromethane (60 ml) was added and the reaction mixture was stirred at −10 to −5 ° C. for 30 minutes. Stir. Triethylamine (1.99 ml, 14.3 mmol) is added dropwise over 10 minutes and the reaction mixture is stirred at 0 ° C. for 1 hour. The reaction mixture is extracted with dichloromethane. The organic phase is washed with aqueous 5% sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (50: 50: 0.5 acetone / hexane / ammonium hydroxide) affords the title compound (8.27 g) as a white foam. Elemental Analysis for C ₃₅ H ₅₆ N ₂ O ₁₁ : calculated. C, 61.75; H, 8. 29; N, 4.11; Found: C, 62.25; H, 8.50; N, 4.28.

Example 178

A compound of Formula 9: L is CO, T is NH, and R is CH ₂ -CH = CH- (3-quinolyl)]

Step 178a: a compound of Formula 3; R ^c Is acetyl, L is CO, T is NH and R is -CH ₂ -CH = CH- (3-quinolyl)

A mixture of compound from Example 177 (46.36 g, 68.2 mmol), palladium (II) acetate (3.055 g, 13.6 mmol) and tri-o-tolylphosphine (8.268 g, 27.2 mmol) in acetonitrile (400 ml) was prepared. Flush with nitrogen. To this solution is added 3-bromoquinoline (18.45 ml, 136 mmol) and triethylamine (18.92 ml, 13.6 mmol) via syringe. The reaction mixture is heated at 50 ° C. for 1 hour and stirred at 90 ° C. for 4 days. The reaction mixture is dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered and then concentrated in vacuo. Chromatography on silica gel (50: 50: 0.5 acetone / hexane / ammonium hydroxide) affords the title compound (46.56 g) as a white foam. MS m / e 808 (M + H) ⁺ .

Step 178b: Compound of Formula 9: L is CO and T is NH and R is -CH ₂ CH = CH- (3-quinolyl)

Example 1 By stirring overnight in methanol according to the procedure of step g, deprotection of the sample of the compound prepared in step 178a (42.43 g) is carried out to give the title product (32.95 g). MS m / e 766 (M + H) ⁺ .

Example 179

Compound of Formula 9: L is CO and T is N (CH ₃ ) And R is -CH ₂ -CH = CH ₂ to be

Step 179a: compound 18 from scheme 4; R ^* Is methyl and R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

Example 102, Sample compound from step 102b [Compound 12 from Scheme 3a, wherein R is —CH ₂ CH═CH ₂ and R ^p is benzoyl; 320 mg, 0.400 mmol] is dissolved in acetonitrile (10 ml) and the solution is flushed with nitrogen. Aqueous methylamine (40%, 0.344 ml) is added and the reaction mixture is stirred under nitrogen for 4 days. The reaction mixture is extracted with ethyl acetate and the organic phase is washed with 5% aqueous sodium bicarbonate and brine, dried over sodium sulfate and then concentrated in vacuo to give a white foam. Chromatography on silica gel (30% acetone-hexane) affords the title compound (277 mg) as a white solid. MS m / e 757 (M + H) ⁺ .

Step 179b: compound of Formula 9; L is CO and T is N (CH ₃ ) And R is -CH ₂ CH = CH ₂ to be

By stirring overnight in methanol according to the procedure of Example 1, step g, the compound sample (110 mg) prepared in step 179a was deprotected to give the title compound (48 mg). Elemental analysis for C ₃₄ H ₅₆ N ₂ O ₁₀ : Calcd: C, 62.56; H, 8. 65; N, 4.29; Found: C, 62.23; H, 8. 72; N, 4.13.

Example 180

A compound of formula 9; L is CO and T is N (CH ₃ ) And R is -CH ₂ CH = CH- (3-quinolyl)

The procedure of Example 178 is carried out except that the starting material compound (from Example 177) is replaced with the compound of Example 179, step a to prepare the title compound.

Example 181

Compound of Formula 9: L is CO and T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) And R is -CH ₂ -CH = CH ₂ to be

Step 181a: Compound 18 from Scheme 4; R ^* is 2- (dimethylamino) ethyl, R is -CH ₂ CH = CH ₂ and R ^p is benzoyl

Except for replacing methylamine with N, N-dimethylethylenediamine, the procedure of Example 179 was followed to yield the title compound (285 mg). MS m / e 814 (M + H) ⁺ .

Step 181b: Compound of Formula 9: L is CO and T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) And R is -CH ₂ -CH = CH ₂ to be

By heating overnight in methanol according to the procedure of Example 1, step g, the compound sample (110 mg) prepared in step 181a was deprotected to give the title product (28 mg).

Example 182

Compound of Formula 9: L is CO and T is N (CH ₂ CH ₂ N (CH ₃ ) ₂ ) And R is -CH ₂ -CH = CH- (3-quinolyl)

The procedure of Example 178 is carried out except that the starting material compound (from Example 177) is replaced with the compound of Example 180, step a to prepare the title compound (33.4 mg).

Example 183

Compound of Formula 9: L is CO and T is N (CH ₂ CH = CH ₂ ) And R is -CH ₂ -CH = CH ₂ to be

Step 183a: compound 18 from scheme 4; R ^* -CH ₂ CH = CH ₂ And R is -CH ₂ CH = CH ₂ And R ^p Is benzoyl

Except for replacing methylamine with allylamine, the procedure of Example 179 is followed to yield the title compound.

Step 183b: Compound of Formula 9: L is CO and T is N (CH ₂ CH = CH ₂ ) And R is -CH ₂ -CH = CH ₂ to be

By heating overnight in methanol according to the procedure of Example 1, step g, the compound sample (78 mg) prepared in step 183a was deprotected to give the title product (33 mg).

Example 184

Compound of Formula 9: L is CO and T is N (CH ₂ CH = CH- (3-quinolyl)) and R is -CH ₂ -CH = CH- (3-quinolyl)

The procedure of Example 178 is carried out except that the starting material compound (from Example 177) is replaced by the compound of Example 183, step a to prepare the title compound. H.Res. Calcd for MS C ₅₄ H ₆₉ N ₄ 0 ₁₀ : 933.5014; Found: 933.5052.

Examples 185 through 219

Except for replacing the 3-bromoquinoline of Example 178 with the following reagents, the procedure of Example 178 is performed to prepare compounds 185 to 219 shown in the following table. Compounds of formula 9, wherein R is CO and T is O, with R substituents as shown in the following table:

Example 220

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ C (O) H

Compound (14.0 g) from Example 102 is dissolved in CH ₂ Cl ₂ (200 ml) and the solution is cooled to −78 ° C. under a nitrogen atmosphere. Ozone is then bubbled into the solution until blue color appears. The reaction is then purged with N ₂ until colorless and dimethylsulfide (14 ml) is added and the reaction mixture is warmed to 0 ° C. After stirring for 90 minutes, the reaction mixture is concentrated under reduced pressure to give a pale yellow foam. This material is dissolved in THF (300 ml) and refluxed with triphenylphosphine (8 g) for 6 hours, then the reaction mixture is concentrated under reduced pressure. Chromatography (1: 1 acetone / hexane to 3: 1 acetone / hexanes with 0.5% TEA) affords the product (6.6 g) as off-white foam. MS (CI) m / e 641 (M + H) ⁺ .

Example 221

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ -Phenyl

Compound (120 mg, 0.187 mmol) and benzylamine (40 μl, 0.366 mmol, 2 equiv) from Example 220 are dissolved in 3 ml of anhydrous dichloromethane. Add molecular sieve (4x) and stir the reaction overnight. The reaction is then filtered and concentrated under reduced pressure. The resulting imine is dissolved in MeOH (5 ml), a catalytic amount of 10% Pd on carbon is added and the reaction is stirred rapidly for 20 hours under 1 atm of H ₂ pressure. The mixture is then filtered through a pad of celite and the solution is concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (84 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.3, 205.6, 170.3, 157.9, 140.2, 128.2, 126.8, 102.4, 83.5, 78.2, 76.9, 75.1, 70.1, 69.5, 65.9, 62.0, 58.4, 53.8, 50.6, 48.2, 45.3, 44.8, 40.1, 39.0, 37.4, 28.2, 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3.

MS (CI) m / e 732 (M + H) ⁺

Example 222

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ -Phenyl

The title compound is prepared from the compound of Example 220 (108 mg, 0.169 mmol) and phenethylamine (42 μl, 0.334 mmol, 2 equiv) using the procedure described for Example 221. Chromatography (SiO ₂ , 5% MeOH / dichloromethane with 0.5% NH ₄ OH) affords the desired material (82 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.1, 205.5, 170.3, 158.0, 140.2, 128.8, 128.2, 125.8, 102.4, 83.6, 78.3, 76.9, 75.1, 70.1, 69.5, 65.9, 61.9, 58.3, 51.5, 50.6, 48.8, 45.2, 44.9, 40.1, 38.9, 37.4, 36.5, 28.2, 22.4, 21.2, 20.6, 18.3, 14.6, 13.6, 13.4, 12.8, 10.3. MS (CI) m / e 746 (M + H) ⁺ . Elemental Analysis for C ₄₀ H ₆₃ N ₃ O ₁₀

Found C 64.26, H 8.47, N 5.43.

Example 223

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ -Phenyl

The title compound is prepared from the compound of Example 220 (100 mg, 0.156 mmol) and 3-phenyl-1-propylamine (40 μl, 0.282 mmol, 1.8 equiv) using the procedure described for Example 221. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.5% NH ₄ OH) affords the desired material (45 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.6, 205.7, 170.4, 158.1, 142.3, 128.4, 128.2, 125.6, 102.4, 83.7, 78.3, 77.0, 75.2, 70.2, 69.5, 65.9, 62.0, 58.4, 50.6, 49.2, 49.0, 45.3, 44.9, 40.2, 39.0, 37.5, 33.7, 31.7, 28.2, 22.4, 21.2, 20.7, 18.3, 14.6, 13.6, 13.5, 12.8, 10.3. MS (CI) m / e 760 (M + H) ⁺ . Elemental Analysis for C ₄₁ H ₆₅ N ₃ O ₁₀

Example 224

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ CH ₂ -Phenyl

The title compound is prepared from the compound of Example 220 (170 mg, 0.266 mmol) and 4-phenyl-1-butylamine (68 μl, 0.431 mmol, 1.6 equiv) using the procedure described for Example 221. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (87 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.6, 205.6, 170.4, 158.1, 142.6, 128.4, 128.1, 125.5, 102.4, 83.7, 78.3, 77.0, 75.2, 70.2, 69.5, 65.9, 61.9, 58.4, 50.6, 50.0, 49.0, 45.3, 44.9, 40.2, 39.0, 37.5, 35.8, 29.7, 29.1, 28.2, 22.4, 21.2, 20.7, 18.3, 14.6, 13.6, 13.5, 12.7, 10.3. MS (CI) m / e 774 (M + H) ⁺ . Elemental Analysis for C ₄₂ H ₆₇ N ₃ O ₁₀

Found C 64.80, H 8.63, N 5.35.

Example 225

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ CH ₂ CH ₂ -(3-quinolyl)

Compound (135 mg, 0.211 mmol) and 3- (3-quinolyl) -1-propylamine (70 mg, 0.376 mmol, 1.8 equiv) from Example 220 are dissolved in 4 ml of anhydrous dichloromethane. Add molecular sieve (4x) and stir the reaction overnight. The reaction is then filtered and concentrated under reduced pressure. The resulting imine is dissolved in MeOH (5 ml) and treated with NaCNBH ₃ (about 100 mg) and sufficient AcOH to cause the bromocresol green indicator to change from blue to yellow. After stirring for 4 hours, the reaction mixture is poured into saturated NaHCO ₃ solution and extracted with dichloromethane. The organic fraction is washed with saturated NaHCO ₃ , H ₂ O and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane with 0.5% NH ₄ OH to 10% MeOH / dichloromethane with 1% NH ₄ OH) affords the desired material (71 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.8, 205.7, 170.5, 158.2, 152.2, 146.8, 135.0, 134.2, 129.1, 128.4, 128.2, 127.4, 126.4, 102.5, 83.8, 78.4, 77.2, 75.2, 70.2, 69.6, 65.9, 62.0, 58.4, 50.7, 49.5, 49.1, 45.4, 44.9, 40.2, 39.1, 37.6, 31.4, 30.9, 28.3, 22.6, 21.3, 20.7, 18.3, 14.7, 13.6, 13.5, 12.8, 10.3. MS (CI) m / e 811 (M + H) ⁺ . Elemental Analysis for C ₄₄ H ₆₆ N ₄ O ₁₀

Found C 65.50, H 8.51, N 6.66.

Example 226

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ -(3-quinolyl)

The title compound is prepared from the compound of Example 220 (150 mg, 0.234 mmol) and 3- (aminomethyl) quinoline (100 mg, 0.633 mmol, 2.7 equiv) using the procedure described for Example 225. Chromatography (SiO ₂ , 5% MeOH / dichloromethane with 0.5% NH ₄ OH) affords the desired material (82 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.8, 205.5, 170.4, 158.1, 151.6, 147.3, 134.5, 133.0, 129.0, 128.7, 128.0, 127.6, 126.3, 102.4, 83.7, 78.3, 76.9, 75.1, 70.1, 69.4, 65.8, 61.8, 58.4, 51.3, 50.5, 48.5, 45.3, 44.8, 40.1, 39.0, 37.4, 28.2, 22.3, 21.2, 20.6, 18.2, 14.6, 13.6, 13.4, 12.7, 10.2. MS (CI) m / e 783 (M + H) ⁺ . Elemental Analysis for C ₄₂ H ₆₂ N ₄ O ₁₀

Found C 64.32, H 8.01, N 7.11.

The 3- (aminomethyl) quinoline reagent is prepared as follows:

Step 226a: 3- (hydroxymethyl) quinoline

Quinoline 3-carboxaldehyde (1.0 g, 6.37 mmol) is dissolved in 20 ml of EtOH and treated with NaBH ₄ (70 mg). After stirring for 1 hour, the solution is treated with 2 ml of 1N HCl and stirred for 10 minutes, then the reaction mixture is treated with sufficient 1N NaOH to make the solution basic. The reaction mixture is extracted with Et ₂ O and the organic fractions are washed with H ₂ O and brine. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford the title compound. MS (CI) m / e 160 (M + H) ⁺ .

Step 226b: 3- (azidomethyl) quinoline

3- (hydroxymethyl) quinoline (0.36 g, 2.26 mmol) and triphenyl phosphine (621 mg, 2.37 mmol, 1.05 equiv) are dissolved in 10 ml of dry THF and then cooled to 0 ° C. The reaction mixture is treated with diphenylphosphoryl azide (570 μl, 2.63 mmol, 1.16 equiv) and then diethylazodicarboxylate (405 μl, 2.57 mmol, 1.14 equiv) is added dropwise. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is then concentrated under reduced pressure. Chromatography (SiO ₂ , 2: 1 hexanes / EtOAc) affords the desired material (350 mg) as a colorless oil. MS (CI) m / e 185 (M + H) ⁺ .

Step 226c: 3- (aminomethyl) quinoline

3- (azidomethyl) quinoline (250 mg, 1.36 mmol) and triphenylphosphine (880 mg, 3.36 mmol, 2.5 equiv) are dissolved in 10 ml THF. The reaction mixture is treated with 0.5 ml of H ₂ O and refluxed for 6 hours. The reaction mixture is cooled and partitioned between Et ₂ O and 1N HCl. The aqueous fraction is then treated with 1N NaOH until basic and extracted with EtOAc. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford the title compound (104 mg) as a brown oil. MS (CI) m / e 159 (M + H) ⁺ .

Example 227

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHCH ₂ -(6-quinolyl)

The title compound is prepared from the compound of Example 220 (116 mg, 0.181 mmol) and 3- (aminomethyl) quinoline (40 mg, 0.25 mmol, 1.4 equiv) using the procedure described for Example 221. Chromatography (SiO ₂ , 5% MeOH / dichloromethane with 0.5% NH ₄ OH) affords the desired material (62 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.7, 205.6, 170.4, 158.1, 149.8, 147.8, 138.9, 136.0, 130.3, 129.4, 128.3, 126.2, 121.0, 102.5, 83.7, 78.4, 77.0, 75.2, 70.2, 69.5, 65.9, 62.1, 58.5, 53.7, 50.6, 48.6, 45.4, 44.9, 40.2, 39.1, 37.5, 28.3, 22.4, 21.3, 20.7, 18.3, 14.7, 13.7, 13.5, 12.8, 10.3. MS (CI) m / e 783 (M + H) ⁺ . Elemental Analysis for C ₄₂ H ₆₂ N ₄ O ₁₀

The 6- (aminomethyl) quinoline reagent is prepared as follows:

Step 227a: 6- (hydroxymethyl) quinoline

Quinoline 6-carboxylic acid (1.73 g, 10.0 mmol) was suspended in 40 ml THF at 0 ° C. under N ₂ , treated with N-ethyl morpholine (1.3 ml, 10.2 mmol, 1.02 equiv) followed by ethyl chloroformate (1.1 ml, 11.5 mmol, 1.15 equiv) is added dropwise. After stirring for 15 minutes, the solution is filtered and the resulting salt is washed with additional THF. The filtrate is then added to a solution of NaBH ₄ (760 mg, 20 mmol) in H ₂ O (50 ml) which is stirred rapidly. After stirring for 20 minutes, the reaction mixture is quenched with saturated NH ₄ Cl solution and extracted with EtOAc (2 × 50 ml). The organic fractions are washed with brine, dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Chromatography (SiO ₂ , 1: 3 hexanes / EtOAc) affords the desired material (1.30 g) as a colorless oil. MS (CI) m / e 160 (M + H) ⁺ .

Step 227b: 6- (azidomethyl) quinoline

6- (hydroxymethyl) quinoline (0.51 g, 3.21 mmol) and triphenyl phosphine (880 mg, 3.36 mmol, 1.05 equiv) are dissolved in 15 ml of dry THF and then cooled to 0 ° C. The reaction mixture is treated with diphenylphosphoryl azide (0.81 ml, 3.74 mmol, 1.16 equiv) and then diethylazodicarboxylate (0.57 ml, 3.62 mmol, 1.13 equiv) is added dropwise. The reaction mixture is allowed to warm to room temperature overnight. The reaction mixture is then concentrated under reduced pressure. Chromatography (SiO ₂ , 30% EtOAc / hexanes) affords the desired material (320 mg) as a colorless oil. MS (CI) m / e 185 (M + H) ⁺ .

Step 227c: 6- (aminomethyl) quinoline

6- (azidomethyl) quinoline (320 mg) and triphenylphosphine (880 mg) are dissolved in 7 ml THF. The reaction mixture is treated with 0.5 ml of H ₂ O and refluxed for 7 hours. The reaction mixture is cooled and partitioned between Et ₂ O and 1N HCl. The aqueous fraction is then treated with 1N NaOH until basic and extracted with EtOAc. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford the title compound (70 mg) as a brown oil. MS (CI) m / e 159 (M + H) ⁺ .

Example 228

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NO (phenyl)

Compound (200 mg, 0.313 mmol) and O-phenylhydroxylamine.HCl (138 mg, 0.948 mmol, 3.0 equiv) from Example 220 are dissolved in 4 ml of MeOH. Triethylamine (118 μl, 0.847 mmol, 2.7 equiv) is added and the reaction is stirred at reflux for 3 hours. The reaction is cooled and quenched with saturated NaHCO ₃ solution. The reaction mixture is extracted with dichloromethane (2 x 25 ml) and the combined organic fractions are washed with H ₂ O and brine. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (150 mg, 3: 2 mixture of oxime isomers) as a purple solid.

¹³ C NMR (CDCl ₃ ) δ 218.1, 217.4, 205.0, 169.9, 169.8, 159.1, 159.1, 157.9, 157.6, 152.9, 150.8, 129.1, 129.0, 122.2, 122.1, 114.8, 114.6, 103.2, 103.1, 83.5, 83.4, 79.8, 79.6, 77.1, 77.0, 76.9, 70.2, 69.6, 65.8, 60.3, 58.1, 58.0, 58.0, 50.9, 50.9, 46.6, 46.6, 44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 37.4, 28.2, 22.2, 22.1, 21.1, 21.1, 20.5, 20.1, 18.0, 17.9, 14.6, 14.5, 14.5, 14.4, 13.5, 13.5, 10.4, 10.2. MS (Cl) m / e 732 (M + H) ⁺ .

Elemental Analysis for C ₃₈ H ₅₇ N ₃ O ₁₁ :

Found: C: 62.30, H: 7.76, N: 5.74.

Example 229

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(Phenyl)

The title compound is prepared from the compound of Example 220 (201 mg, 0.314 mmol) and O-benzylhydroxylamine.HCl (150 mg, 0.940 mmol, 3.0 equiv) using the procedure described for Example 228. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (170 mg, 2: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.1, 217.2, 205.1, 170.0, 169.8, 158.0, 157.9, 150.5, 147.8, 138.1, 137.8, 128.4, 128.0, 127.8, 103.3, 103.3, 83.7, 83.7, 79.6, 79.5, 77.5, 77.3, 77.0, 76.9, 76.1, 76.0, 70.4, 69.7, 66.0, 60.5, 58.2, 58.1, 58.0, 51.0, 51.0, 46.8, 46.5, 45.0, 44.9, 40.3, 38.9, 38.7, 37.6, 28.4, 22.5, 22.4, 21.3, 20.6, 20.2, 18.2, 18.1, 14.8, 14.7, 14.6, 14.4, 13.7, 13.7, 10.6, 10.5, MS (Cl) m / e 746 (M + H) ⁺ .

Elemental Analysis for C ₃₉ H ₅₉ N ₃ O ₁₁ :

Found: C: 62.89, H: 8.04, N: 5.42.

Example 230

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(4-NO ₂ -Phenyl)

The title compound is prepared from the compound of Example 220 (200 mg, 0.313 mmol) and O- (4-nitrobenzyl) hydroxylamine.HCl (192 mg, 0.938 mmol, 3.0 equiv) using the procedure described for Example 228. . Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (184 mg, 2: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.2, 217.3, 205.0, 169.9, 169.7, 157.8, 151.2, 148.7, 147.4, 145.7, 145.5, 128.4, 128.1, 123.6, 123.5, 103.2, 83.6, 83.5, 79.6, 79.4, 77.1, 76.9, 76.8, 74.5, 74.3, 70.2, 69.6, 65.8, 60.2, 58.0, 57.9, 57.8, 51.0, 50.9, 46.8, 46.6, 44.9, 44.7, 40.2, 38.7, 38.5, 37.5, 37.4, 28.2, 22.4, 22.2, 21.2, 21.2, 20.5, 20.1, 18.1, 17.9, 14.8, 14.5, 14.4, 13.5, 10.5, 10.3. MS (Cl) m / e 791 (M + H) ⁺ .

Example 231

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ (4-quinolyl)

Compound (200 mg, 0.313 mmol) and O- (4-quinolyl) methylhydroxylamine (200 mg, 0.86 mmol, 2.7 equiv) from Example 220 are dissolved in 4 ml of MeOH. Catalytic pTSA.H ₂ O is added and the reaction is stirred at reflux for 2 hours. Cool the reaction and quench with saturated NaHCO ₃ solution. The reaction mixture is extracted with dichloromethane (2 x 25 ml) and the combined organic fractions are washed with H ₂ O and brine. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (226 mg, 2: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 218.1, 217.3, 205.0, 205.0, 170.0, 169.8, 158.0, 157.9, 151.3, 150.3, 148.7, 148.0, 143.2, 143.2, 130.1, 130.0, 129.1, 129.1, 126.7, 126.2, 126.2, 123.4, 123.3, 119.9, 119.6, 103.2, 83.7, 83.6, 79.7, 79.5, 77.4, 77.2, 77.1, 77.0, 76.9, 72.6, 72.3, 70.3, 69.6, 65.8, 60.3, 58.1, 58.0, 57.9, 51.0, 50.9, 46.8, 46.6, 44.9, 44.8, 40.2, 38.8, 38.5, 37.5, 37.5, 28.2, 22.4, 22.2, 21.2, 21.2, 20.5, 20.2, 18.1, 18.0, 14.9, 14.6, 14.5, 13.6, 13.6, 10.6, 10.3. MS (Cl) m / e 797 (M + H) ⁺ .

Elemental Analysis for C ₄₂ H ₆₀ N ₄ O ₁₁ :

Found: C: 63.46, H: 7.80, N: 6.87.

O- (4-quinolyl) methylhydroxylamine reagent is prepared as follows:

Step 231a: N- (4-quinolyl) methoxyphthalimide

4- (hydroxymethyl) quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (2.27 g, 8.66 mmol, 1.15 equiv) and N-hydroxyphthalimide (1.42 g, 8.71 mmol, 1.15 equiv) Dissolve in 40 ml of THF. Diethylazodicarboxylate (1.44 ml, 9.15 mmol, 1.21 equiv) is then added dropwise and the reaction is stirred overnight. The reaction mixture is then diluted with 50 ml of EtO ₂ and filtered. The resulting solid is dissolved in dichloromethane and washed with 1N NaOH, H ₂ O and brine. The organic fractions are dried over Na ₂ S0 ₄ and concentrated under reduced pressure to afford the title compound (2.03 g) as a lint white solid. MS (CI) m / e 305 (M + H) ⁺ .

Step 231b: O- (4-quinolyl) methylhydroxyamine

N- (4-quinolyl) methoxy phthalimide (2.00 g) is suspended in 95% EtOH and hydrazine (0.30 ml) is added. The reaction mixture is stirred for 3 hours and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydride is filtered off. The filtrate is concentrated under reduced pressure to give the title compound (1.44 g) as a yellow oil. MS (CI) m / e 175 (M + H) ⁺ .

Example 232

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(2-quinolyl)

The title compound is prepared from the compound of Example 220 (206 mg, 0.322 mmol) and O- (2-quinolyl) methylhydroxylamine (120 mg, 0.681 mmol, 2.1 equiv) using the procedure described for Example 231. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (185 mg, 3: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 217.9, 217.2, 204.9, 204.9, 169.9, 169.8, 159.0, 158.9, 157.8, 151.0, 148.7, 147.6, 136.5, 129.3, 129.2, 129.0, 127.5, 126.1, 126.0, 119.8, 119.6, 103.1, 83.5, 79.6, 79.4, 77.3, 77.0, 76.9, 76.9, 76.8, 76.7, 70.2, 69.5, 65.8, 60.4, 58.0, 58.0, 50.9, 46.5, 46.4, 44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 37.4, 28.2, 22.3, 22.2, 21.2, 21.1, 20.5, 20.1, 18.1, 18.0, 14.5, 14.4, 14.3, 13.5, 10.4, 10.3. MS (Cl) m / e 797 (M + H) ⁺ .

O- (2-quinolyl) methylhydroxylamine reagent is prepared as follows:

Step 232a: N- (2-quinolyl) methoxyphthalimide

2- (hydroxymethyl) quinoline (1.20 g, 7.55 mmol), triphenyl phosphine (1.00 g, 6.29 mmol, 1.05 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) Dissolve in 25 ml of THF. Then diethylazodicarboxylate (1.09 ml, 6.93 mmol, 1.10 equiv) is added dropwise and the reaction is stirred overnight. The reaction mixture is filtered to give a white solid. The filtrate is concentrated and triturated with Et ₂ O to afford a second material. It is combined with the original solid and recrystallized from EtOH to give the desired product (1.53 g) as a lint white solid. MS (CI) m / e 305 (M + H) ⁺ .

Step 232b: O- (2-quinolyl) methylhydroxyamine

N- (2-quinolyl) methoxy phthalimide (1.53 g) is suspended in 95% EtOH and hydrazine (0.30 ml) is added. The reaction mixture is stirred for 5 hours and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydrazide is then filtered off. The filtrate is concentrated under reduced pressure to give the title compound (0.91 g) as a yellow oil. MS (CI) m / e 175 (M + H) ⁺ .

Example 233

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(3-quinolyl)

The title compound is prepared from the compound of Example 220 (250 mg, 0.391 mmol) and O- (3-quinolyl) methylhydroxylamine (160 mg, 0.909 mmol, 2.3 equiv) using the procedure described for Example 231. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (202 mg, 2: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 217.9, 217.1, 205.0, 169.9, 169.7, 157.9, 157.8, 151.0, 150.9, 150.8, 148.4, 147.8, 135.4, 135.2, 130.6, 130.5, 129.3, 129.2, 128.0, 127.9, 127.9, 126.6, 126.5, 103.2, 83.6, 83.5, 79.5, 79.4, 77.2, 76.9, 76.7, 73.7, 73.4, 70.3, 69.6, 65.9, 60.3, 58.1, 57.9, 51.0, 50.9, 46.7, 46.4, 44.9, 44.7, 40.2, 38.8, 38.6, 37.5, 28.2, 22.4, 22.2, 21.2, 20.4, 20.1, 18.1, 18.0, 14.7, 14.6, 14.4, 14.3, 13.6, 13.5, 10.5, 10.3. MS (Cl) m / e 797 (M + H) ⁺ .

Elemental Analysis for C ₄₂ H ₆₀ N ₄ O ₁₁

Found: C: 63.00, H: 7.56, N: 6.79

O- (3-quinolyl) methylhydroxyamine reagent is prepared as follows:

Step 233a: N- (3-quinolyl) methoxyphthalimide

3- (hydroxymethyl) quinoline (400 mg, 2.52 mmol), triphenyl phosphine (692 mg, 2.64 mmol, 1.05 equiv) and N-hydroxyphthalimide (430 mg, 2.64 mmol, 1.05 equiv) in 10 ml of dry THF Dissolve. Diethylazodicarboxylate (0.44ml, 2.80mmol, 1.11 equiv) is then added dropwise and the reaction is stirred overnight. The reaction mixture is left in the freezer for 2 hours and then filtered to afford the desired product (0.69 g) as a lint white solid. MS (CI) m / e 305 (M + H) ⁺ .

Step 233b: O- (3-quinolyl) methylhydroxyamine

N- (3-quinolyl) methoxy phthalimide (0.69 g) is suspended in 95% EtOH and hydrazine (0.10 ml) is added. The reaction mixture is stirred overnight and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydrazide is then filtered off. The filtrate is concentrated under reduced pressure to afford the title compound (0.42 g) as a yellow oil. MS (CI) m / e 175 (M + H) ⁺ .

Example 234

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(6-quinolyl)

The title compound is prepared from the compound of Example 220 (120 mg, 0.186 mmol) and O- (6-quinolyl) methylhydroxylamine (92 mg, 0.529 mmol, 2.8 equiv) using the procedure described for Example 231. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (89 mg, 3: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 217.9, 217.1, 204.9, 169.8, 169.6, 157.8, 157.7, 150.6, 150.1, 148.0, 147.8, 136.1, 136.1, 129.6, 129.4. 129.3, 128.0, 126.6, 126.3, 121.0, 103.0, 83.5, 83.4, 79.4, 79.3, 77.4, 77.0, 76.8, 76.7, 76.6, 75.5, 75.3, 70.1, 69.5, 65.7, 60.2, 58.0, 57.9, 57.8, 50.8, 46.6, 46.3, 44,8, 44.6, 40.1, 38.6, 38.4, 37.3, 28.1, 22.3, 22.1, 21.1, 20.4, 20.0, 18.0, 17.8, 14.7, 14.5, 14.3, 13.4, 10.4, 10.2. MS (CI) m / e 797 (M + H) ⁺ .

Elemental Analysis for C ₄₂ H ₆₀ N ₄ O ₁₁

Found: C 63.03, H 7.60, N 6.69.

O- (6-quinolyl) methylhydroxylamine reagent is prepared as follows:

Step 234a: N- (6-quinolyl) methoxyphthalimide

6- (hydroxymethyl) quinoline (520 mg, 3.27 mmol), triphenyl phosphine (900 mg, 3.44 mmol, 1.05 equiv) and N-hydroxyphthalimide (560 mg, 3.43 mmol, 1.05 equiv) in 25 ml of dry THF Dissolve. Diethylazodicarboxylate (574 μl, 3.63 mmol, 1.11 equiv) is then added dropwise and the reaction is stirred overnight. The reaction mixture is filtered to give a white solid. The filtrate is concentrated and triturated with Et ₂ O to afford a second material. It is combined with the original solid and recrystallized from EtOH to give the desired product (782 mg) as a lint white solid. MS (CI) m / e 305 (M + H) ⁺ .

Step 234b: O- (2-quinolyl) methylhydroxyamine

N- (2-quinolyl) methoxy phthalimide (782 mg) is suspended in 95% EtOH and hydrazine (0.15 ml) is added. The reaction mixture is stirred overnight and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydrazide is then filtered off. The filtrate is concentrated under reduced pressure to give the title compound (480 mg) as a yellow oil. MS (CI) m / e 175 (M + H) ⁺ .

Example 235

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(1-naphthyl)

The title compound is prepared from the compound of Example 220 (117 mg, 0.183 mmol) and O- (1-naphthyl) methylhydroxylamine (80 mg, 0.462 mmol, 2.5 equiv) using the procedure described for Example 231. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.1% NH ₄ OH) affords the desired material (112 mg, 2: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 217.8, 217.0, 205.0, 169.9, 169.7, 157.9, 157.8, 150.3, 147.7, 133.7, 133.1, 131.8, 128.7, 128.6, 128.4, 127.1, 126.8, 126.2, 125.6, 125.3, 124.1, 103.1, 103.1, 83.6, 79.5, 79.3, 77.2, 77.0, 76.9, 74.7, 74.3, 70.3, 69.6, 65.9, 60.5, 58.1, 58.0, 51.0, 50.9, 46.6, 46.3, 44.9, 44.8, 40.2, 38.8, 38.6, 37.5, 28.3, 22.4, 22.3, 21.2, 20.5, 20.0, 14.6, 14.5, 14.1, 13.6, 10.5, 10.3.

MS (CI) m / e 796 (M + H) ⁺ .

Elemental Analysis for C ₄₃ H ₆₁ N ₃ O ₁₁

Found: C 64.91, H 7.80, N 5.06

O- (1-naphthyl) methylhydroxylamine reagent is prepared as follows:

Step 235a: N- (1-naphthyl) methoxyphthalimide

1- (hydroxymethyl) naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv) and N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv) Dissolve in 25 ml of THF. Diethylazodicarboxylate (1.09 ml, 6.93 mmol, 1.09 equiv) is then added dropwise and the reaction is stirred overnight. The reaction mixture is diluted with 25 ml Et ₂ O and placed in the freezer for 2 hours. The reaction mixture is then filtered to give a white solid. Recrystallization from EtOH gives the desired product (1.21 g) as a white solid. MS (CI) m / e 321 (M + NH ₄ ) ⁺ .

Step 235b: O- (1-naphthyl) methylhydroxyamine

N- (1-naphthyl) methoxy phthalimide (1.21 g) is suspended in 95% EtOH and hydrazine (0.20 ml) is added. The reaction mixture is stirred overnight and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydrazide is then filtered off. The filtrate is concentrated under reduced pressure to afford the title compound (480 mg) as a colorless oil. MS (CI) m / e 174 (M + H) ⁺ .

Example 236

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NOCH ₂ -(2-naphthyl)

The title compound is prepared from the compound of Example 220 (122 mg, 0.191 mmol) and O- (2-naphthyl) methylhydroxylamine (62 mg, 0.358 mmol, 1.9 equiv) using the procedure described for Example 231. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.1% NH ₄ OH) affords the desired material (100 mg, 3: 1 mixture of oxime isomers) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 217.8, 217.0, 204.9, 169.8, 169.6, 157.8, 157.7, 150.3, 147.8, 135.4, 135.1, 133.2, 132.9, 128.0, 127.9, 127.9, 127.5, 127.0, 126.7, 126.1, 125.8, 125.7, 125.7, 125.6, 103.1, 83.5, 83.5, 79.4, 79.3, 77.1, 76.9, 76.8, 76.1, 75.9, 70.2, 69.5, 65.8, 60.3, 58.0, 57.9, 57.9, 50.9, 46.6, 46.3, 44.8, 44.7, 40.1, 38.7, 38.5, 37.4, 28.1, 22.3, 22.1, 21.1, 20.4, 20.0, 18.0, 17.9, 14.6, 14.5, 14.4, 14.2, 13.5, 10.4, 10.2. MS (CI) m / e 796 (M + H) ⁺ .

Elemental Analysis for C ₄₃ H ₆₁ N ₃ O ₁₁

Found: C 64.59, H 7.72, N 5.14

O- (2-naphthyl) methylhydroxylamine reagent is prepared as follows:

Step 236a: N- (2-naphthyl) methoxyphthalimide

2- (hydroxymethyl) naphthalene (1.00 g, 6.33 mmol), triphenyl phosphine (1.73 g, 6.60 mmol, 1.04 equiv.) And N-hydroxyphthalimide (1.08 g, 6.63 mmol, 1.05 equiv.) Dissolve in 25 ml of THF. Diethylazodicarboxylate (1.09 ml, 6.93 mmol, 1.09 equiv) is then added dropwise and the reaction is stirred overnight. The reaction mixture is left in the freezer for 2 hours and then filtered and washed with Et ₂ O to afford the product (1.38 g) as a white solid. MS (CI) m / e 321 (M + NH ₄ ) ⁺ .

Step 236b: O- (2-naphthyl) methylhydroxylamine

N- (2-naphthyl) methoxy phthalimide (1.38 g) is suspended in 95% EtOH and hydrazine (0.25 ml) is added. The reaction mixture is stirred overnight and then filtered. The filtrate is concentrated under reduced pressure and then dissolved in a small amount of dichloromethane. A small amount of residual phthalhydride is then filtered off. The filtrate is concentrated under reduced pressure to give the title compound (821 mg) as a colorless oil. MS (CI) m / e 174 (M + H) ⁺ .

Example 237

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHOCH ₂ -(Phenyl)

Compound (120 mg, 0.161 mmol) from Example 229 is dissolved in MeOH (5 ml) and treated with NaCNBH ₃ (about 120 mg) and sufficient AcOH so that the bromocresol green indicator turns from blue to yellow. After stirring for 20 hours, the reaction mixture is poured into saturated NaHCO ₃ solution and extracted with dichloromethane. The organic fraction is washed with saturated NaHCO ₃ , H ₂ O and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (51 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 219.0, 205.7, 170.5, 157.8, 138.3, 128.1, 127.5, 102.5, 83.6, 78.6, 77.0, 75.6, 75.2, 70.2, 69.5, 66.0, 58.8, 58.3, 51.4, 50.7, 45.3, 45.0, 40.2, 39.1, 37.7, 28.3, 22.4, 21.3, 20.7, 18.2, 14.7, 13.7, 13.5, 12.8, 10.3. MS (CI) m / e 748 (M + H) ⁺ .

Example 238

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ NHOCH ₂ -(4-NO ₂ -Phenyl)

Compound (64 mg) from Example 230 is dissolved in MeOH (3 ml) and treated with NaCNBH ₃ (about 100 mg) and sufficient HCl to turn the methyl orange indicator to red. After stirring for 20 hours, the reaction mixture is poured into saturated NaHCO ₃ solution and extracted with dichloromethane. The organic fractions are washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (35 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 219.5, 205.5, 170.5, 157.8, 147.2, 146.8, 128.3, 123.4, 102.4, 83.6, 78.6, 76.8, 75.0, 74.3, 70.1, 69.5, 65.8, 58.4, 58.1, 51.3, 50.6, 45.3, 45.0, 40.1, 38.9, 37.7, 28.2, 22.2, 21.2, 20.7, 18.1, 14.6, 13.5, 13.3, 12.8, 10.2. MS (CI) m / e 793 (M + H) ⁺ .

Example 239

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ C (O)-(phenyl)

Step 239a: Compound of Formula 9: L is CO and T is NH and R is -CH ₂ C (OH)-(phenyl)

Compound (550 mg, 0.87 mmol) from Example 220 is dissolved in anhydrous THF (16 ml) and cooled to 0 ° C. under nitrogen. Phenylmagnesium bromide (3.0 M solution in Et ₂ O; 3.0 ml, 6.0 mmol, 6.9 equiv) is added dropwise via syringe. The reaction mixture is stirred for 50 minutes and then quenched by addition of saturated NH ₄ Cl solution. The reaction mixture is extracted with EtOAc and the organic fractions are washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (295 mg) as a white solid. MS (CI) m / e 719 (M + H) ⁺ .

Step 239b: Compound of Formula 18 (Scheme 4): R ^* Is H and R ^p Is Ac and R is -CH ₂ C (OH)-(phenyl)

The compound from the above step (180 mg, 0.250 mmol) is dissolved in 5 ml of anhydrous dichloromethane and treated with acetic anhydride (25 μl, 0.269 mmol, 1.08 equiv). After stirring overnight, the reaction is quenched by addition of saturated NaHCO ₃ solution. The reaction mixture is extracted with dichloromethane and the organic fractions are washed with brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford the desired material (160 mg) as a white solid. MS (CI) m / e 761 (M + H) ⁺ .

Step 239c: Compound of Formula 18 (Scheme 4): R ^* Is H and R ^p Is Ac and R is -CH ₂ C (O)-(phenyl)

DMSO (145 μl, 2.04 mmol, 14 equiv) is added to a cooled (-78 ° C.) solution of oxalyl chloride (145 ml, 1.32 mmol, 9 equiv) in 4 ml of dichloromethane under a nitrogen atmosphere. Compound (113 mg, 0.149 mmol) from the above step was dissolved in 2 ml of dichloromethane and added to the reaction over 15 minutes via cannula. After stirring for 1 hour, Et ₃ N (0.37 ml, 2.65 mmol, 18 equiv) was added to the reaction mixture and the temperature was slowly raised to -20 ° C. It is quenched by addition of 5% KH ₂ PO ₄ solution and extracted with dichloromethane. The organic fractions are washed with 5% KH ₂ PO ₄ , H ₂ O and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. Chromatography (SiO ₂ , 1: 1 acetone / hexane) affords the desired material (42 mg) as a white powder. MS (CI) m / e 759 (M + H) ⁺ .

Step 239d: Compound of Formula 9: L is CO and T is NH and R is -CH ₂ C (O) -phenyl

The compound from the above step is dissolved in 5 ml of MeOH and left overnight. The reaction mixture is concentrated under reduced pressure to afford the title compound (38 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 215.4, 206.1, 194.4, 169.6, 157.7, 135.5, 133.0, 128.5, 127.6, 103.0, 83.8, 79.6, 77.1, 77.1, 70.2, 69.5, 65.9, 65.4, 57.6, 50.9, 46.0, 44.6, 40.2, 38.9, 37.9, 28.4, 22.4, 21.3, 20.2, 18.9, 14.9, 13.9, 13.7, 13.6, 10.5. MS (CI) m / e 717 (M + H) ⁺ .

Example 240

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ C (O)-(4-F-phenyl)

The title compound is prepared from the compound of Example 220 and 4-fluorophenylmagnesium bromide using the reaction sequence of Example 239.

¹³ C NMR (CDCl ₃ ) δ 215.3, 206.0, 192.8, 169.6, 165.7, 157.7, 131.5, 130.2, 115.6, 103.1, 83.8, 79.7, 77.3, 76.8, 70.3, 69.6, 65.8, 65.1, 57.6, 50.9, 46.0, 44.6, 40.2, 38.8, 37.8, 28.3, 22.4, 21.3, 20.2, 18.8, 14.8, 13.9, 13.7, 13.5, 10.4. MS (CI) m / e 735 (M + H) ⁺ .

Example 241

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH = NNHC (O)-(phenyl)

Compound (100 mg, 0.156 mmol) and benzo hydrazide (50 mg, 0.370 mmol, 2.4 equivalents) from Example 220 are dissolved in 3 ml of anhydrous dichloromethane. Add molecular sieve (4x) and stir the reaction overnight. The reaction is filtered and the filtrate is concentrated under reduced pressure. Chromatography (SiO ₂ , 5% MeOH / dichloromethane containing 0.2% NH ₄ OH) affords the desired material (29 mg) as a white solid.

¹³ C NMR (CDCl ₃ ) δ 216.9, 204.2, 169.6, 164.3, 159.0, 148.8, 133.4, 131.2, 128.0, 127.7, 103.2, 83.9, 79.6, 77.6, 76.5, 70.1, 69.5, 65.7, 62.7, 57.8, 50.8, 46.9, 44.4, 40.0, 38.4, 37.3, 28.1, 21.9, 21.1, 20.7, 17.8, 15.0, 14.2, 13.3, 13.1, 10.0. MS (CI) m / e 759 (M + H) ⁺ .

Example 242

Compound of Formula 9: L is CO, T is NH and R is -CH ₂ CH ₂ CH ₂ -(3-quinolyl)

A mixture of compound (230 mg) and 10% Pd / C (50 mg) from Example 104 in 30 ml of methanol and 15 ml of ethyl acetate is flushed with nitrogen and stirred under 1 atm of hydrogen for 22 hours at room temperature. The mixture is filtered and the filtrate is concentrated under reduced pressure. Chromatography on silica gel (5% MeOH / dichloromethane with 0.5% NH ₄ OH) affords the desired material (175 mg) as a white solid. Elemental Analysis for C ₄₂ H ₆₅ N ₃ O ₁₀ : Calculated: C, 65.35; H, 8.49; N, 5.44; Found: C, 65.73; H, 8. 77; N, 5.17.

Example 243

The compound of formula 9: L is CO and T is NH, and R is a -CH ₂ (2- (3-quinolyl) cyclopropyl)

To a solution of diazomethane (0.64 M, 3.12 ml, 2.00 mmol) in ether is added a solution of the compound from Example 104 (153 mg, 0.200 mmol) in dichloromethane (5.0 ml) at 0 ° C. under nitrogen. A small amount (2 mg) of palladium acetate is added and the mixture is stirred for 20 minutes. Another fraction of diazomethane (3 ml) is added and the mixture is stirred for another hour. The solvent is evaporated and the residue is purified by chromatography on silica gel (5% MeOH / dichloromethane with 0.5% NH ₄ OH) to afford the title compound (100 mg) as a white solid. Elemental Analysis for C ₄₃ H ₆₁ N ₃ O ₁₀ : Calculated: C, 66.22; H, 7.88; N, 5.39; Found: C, 66.05; H, 8.08; N, 5.02.

Example 244

Compound of Formula 3: R ^c Is propanoyl, L is CO, T is NH and R is -CH ₂ CH = CH (3-quinolyl)

To a solution of compound (152 mg) from Example 104 in dichloromethane are added propionic anhydride (52 μl) and triethylamine (56 μl) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with ethyl acetate, which is washed with 5% NaHCO ₃ solution and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. The residue is chromatographed on silica gel (1: 1 acetone / hexane) to afford the title compound (119 mg) as a white foam. Elemental Analysis for C ₄₅ H ₆₃ N ₃ O ₁₁ : Calculated: C, 65.75; H, 7.72; N, 5.11; Found: C, 65.67; H, 7.92; N, 4.77.

Example 245

Compound of Formula 3: R ^c Is ethyl succinoyl, L is CO, T is NH and R is -CH ₂ CH = CH (3-quinolyl)

To a solution of compound (153 mg, 0.200 mmol) from Example 104 in dichloromethane (10 ml) is added ethyl succinyl chloride (29 μl) and triethylamine (56 μl) and the mixture is stirred at room temperature for 24 hours. The mixture is diluted with ethyl acetate, which is washed with 5% NaHCO ₃ solution and brine, dried (Na ₂ SO ₄ ) and then concentrated under reduced pressure. The residue is chromatographed on silica gel (1: 1 acetone / hexane) to afford the title compound (110 mg) as a white foam. Elemental analysis for C ₄₈ H ₆₇ N ₃ O ₁₃ H ₂ O: calcd C, 63.21; H, 7.63; N, 4.61; Found: C, 63.08; H, 7. 50; N, 4.20.

Example 246

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-H

Step 246a: Compound 4 from Scheme 1a; V is N-O- (1-isopropoxycyclohexyl) and R is -CH ₂ -C≡C-H and R ^p Is trimethylsilyl

2 ', 4 "-bis-O-trimethylsilylerythromycin A 9- [O- (1-isopropoxycyclohexyl] oxime (100 g, 96.9 mmol; prepared according to the method of US Pat. No. 4,990,602) in THF (200 ml) Anhydrous DMSO (200 ml) was added to the solution under nitrogen and the mixture was cooled to 0 ° C. Propargyl bromide (27 ml, 240 mmol, 80% by weight in toluene) was added to the stirred solution under N ₂ atmosphere, A solution of anhydrous KOH (13.6 g, 240 mmol) in anhydrous DMSO (300 ml) is added over 25 minutes and the mixture is stirred vigorously for 1 hour at 0 ° C. Additional KOH (10.9 g, 190 mmol) and propargyl bromide ( 21 ml, 190 mmol) is added and the mixture is stirred for 1.5 h under N ₂ at 0 ° C. This additional KOH and propargyl bromide are repeated three more times at 1.5 hour intervals, and then the mixture is extracted with ethyl acetate, the organic phase was washed with water and brine, dried (MgSO _4). Removing the sheets in vacuo to give the crude product (108g) and used directly in the next step.

Step 246b: compound 5 from scheme 1a; R is -CH ₂ -C≡C-H

To the compound (108 g) from step 246a in CH ₃ CN (300 ml) is added water (150 ml) and acetic acid (glacial acetic acid, 200 ml) and the mixture is stirred at room temperature for about 20 hours. The solvent is then removed under vacuum at 40 ° C. and the residue is dissolved in EtOAc and washed successively with 5% Na ₂ CO ₃ and brine. The organic phase is then dried over MgSO ₄ , filtered and concentrated to give the title compound (74 g) as a brown foam which is used directly in the next step.

Step 246c: compound 6 from scheme 1a; R is -CH ₂ -C≡C-H

Compound (74 g) resulting from step 246b is dissolved in ethanol (550 ml) and diluted with water (550 ml). Sodium nitrite (33 g, 0.48 mol) is added to this solution and the reaction mixture is stirred at room temperature for 15 minutes. 4M HCl (125 ml, 0.48 mol) is then added at ambient temperature over 15 minutes and the mixture is heated to 70 ° C. for 2 hours and then cooled to room temperature. The mixture is extracted with ethyl acetate and the organic phase is washed with 5% Na ₂ CO ₃ and brine, dried over MgSO ₄ , filtered and then concentrated. The crude product is purified by chromatography on silica gel eluting with 1% methanol / dichloromethane containing 0.5% ammonium hydroxide. This compound is crystallized from acetonitrile to give the title compound (27 g).

Step 246d: Compound 6A from Scheme 1c; R ^p Is acetyl and R is -CH ₂ -C≡C-H

To a solution of 19 g (246 mmol) of compound from step 246c in anhydrous dichloromethane (100 ml) is added 4-dimethylaminopyridine (105 mg) and triethylamine (7.16 ml, 52 mmol). The mixture is cooled to about 15 ° C. in a cold water bath and acetic anhydride (5.5 ml, 59 mmol) is added over 5 minutes. After 5 minutes of stirring at 15 ° C., the cold water bath is removed and the reaction is stirred at ambient temperature for 4 hours. The mixture is diluted with ethyl acetate and washed successively with 5% aqueous sodium carbonate (twice), water (twice) and brine. The organic extract is dried over magnesium sulfate, filtered and concentrated in vacuo. Dry to constant weight using high vacuum to afford the title compound (21 g).

Step 246e: compound 6B from scheme 1c; R ^p Is acetyl and R is -CH ₂ -C≡C-H

To a 0 ° C. solution of compound (21 g, 24.5 mmol) from step 246d in THF (128 ml) and dimethyl sulfoxide (48 ml) is added 1,1′-carbonyldiimidazole (14.3 g, 88.3 mmol). After stirring for 5 minutes, sodium hydride (60% dispersion in mineral oil, 1.3 g, 32.5 mmol) is added little by little over an hour under a nitrogen atmosphere. After the addition is complete, the cooling bath is removed and the mixture is stirred at ambient temperature for 3.5 hours. The reaction is recooled to 0 ° C., diluted with ethyl acetate (about 400 ml) and quenched with 5% aqueous sodium bicarbonate. The organic layer is washed successively with water and brine and then dried over magnesium sulfate. The solution is filtered and the filtrate is concentrated in vacuo. Drying to constant weight gives the title compound (23 g), which is used directly in the next step.

Step 246f: Compound 6C from Scheme 1c; R ^p Is acetyl and R is -CH ₂ -C≡C-H

The pressure vessel containing the compound (23 g, 24 mmol) from step 246e in acetonitrile (250 ml) is cooled to -78 ° C. An equal volume of liquid ammonia (250 ml) is condensed into this reaction vessel and then sealed and warmed to ambient temperature with stirring. After 20 hours, the reaction is recooled to −78 ° C., the pressure vessel is opened and the reaction is allowed to warm to ambient temperature with stirring. Once all liquid ammonia is evaporated, acetonitrile is removed in vacuo and the residue is dried to constant weight to give the title compound (21 g).

Step 246g: Compound 6D from Scheme 1c; R ^p Is acetyl and R is -CH ₂ -C≡C-H

To a 0 ° C. suspension of compound (21 g) from step 246f in 1: 1 ethanol / water (200 ml) add 4M hydrochloric acid (125 ml) over 10 minutes. After removal of the cooling bath, the reaction solution is stirred at ambient temperature for 26 hours. The mixture is diluted with water, cooled to 0 ° C. and made basic to pH 10 with 2N sodium hydroxide. The mixture is then extracted with ethyl acetate (400 ml) and the organic layer is washed with brine. The organic extract is dried over magnesium sulfate, filtered and concentrated in vacuo. Drying to constant weight yields crude product (18 g) which is crystallized from ethyl acetate / hexanes to give pure title compound (8.5 g).

Step 246h: Compound 6E from Scheme 1c; R ^p Is acetyl and R is -CH ₂ -C≡C-H

To a −10 ° C. solution of N-chlorosuccinimide (2.3 g, 0.017 mol) in dichloromethane (100 ml) is added methyl sulfide (1.47 ml, 0.021 mol) over 5 minutes. The reaction is stirred at −10 ° C. for 10 minutes. A solution of compound (8.3 g, 0.012 mol) from step 246 g in dichloromethane (100 ml) is added for 30 minutes, then the mixture is stirred at -10 ° C for 25 minutes. Triethylamine (1.6 ml, 0.021 mol) is added for 5 minutes and the reaction is stirred at -10 ° C for 50 minutes. The reaction is then quenched with 5% aqueous sodium bicarbonate (50 ml) and extracted with dichloromethane (300 ml). The organic layer is washed with 5% aqueous sodium bicarbonate, then brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. The crude product is eluted with 30% acetone / hexanes and then purified by column chromatography on silica gel eluting with 50% acetone / hexanes to give the title compound (7.35 g).

Step 246i: Compound of Formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-H

A sample of compound (72 g) from step 246h is dissolved in methanol (8 ml) and stirred at ambient temperature for 18 hours. After concentration in vacuo and drying to constant weight under high vacuum, 65 mg of pure title compound are obtained. High resolution FAB MS: calculated m / e = 637.3700 for (M + H) ⁺ of C ₃₃ H ₅₃ N ₂ O ₁₀ ; Found m / e = 637.3718.

Example 247

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (3-quinolyl)

Step 247a: Compound 6E from Scheme 1c; R is -CH ₂ -C≡C- (3-quinolyl)

A pressure tube equipped with a stirring rod was filled with dichlorobis (triphenylphosphine) palladium (II) (6.2 mg), degassed triethylamine (2.5 ml) and degassed N, N-dimethylformamide (0.5 ml). Next, 3-bromoquinoline (93 μl) and a sample of the compound (300 mg) from step 246h are filled, and finally copper (II) iodide (0.84 mg) is filled. The reaction is sealed under nitrogen atmosphere and heated to 60 ° C. for 2 hours. After cooling to room temperature, the reaction is diluted with 1: 1 ether / ethyl acetate and washed three times with water and brine. The organic extract is dried over magnesium sulfate, filtered and concentrated in vacuo. Drying in high vacuum yields 374 mg of crude product. The crude product is purified by silica gel chromatography using 30% acetone / hexanes to give the title compound (280 mg, 78%). MS (APCI) ⁺ m / e 806 (M + H) ⁺ .

Step 247b: a compound of Formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (3-quinolyl)

Compound (270 mg) from step 247a is dissolved in methanol and stirred at ambient temperature for 18 hours. After concentration in vacuo and drying to high weight under high vacuum, 260 mg of crude product are obtained. Purification by silica gel chromatography eluting with 98: 1: 1 dichloromethane / methanol / ammonium hydroxide gave 221 mg of the title compound. High resolution FAB MS: calculated m / e = 764.4122 for (M + H) ⁺ of C ₄₂ H ₅₈ N ₃ O ₁₀ ; Found m / e = 764.4121.

Example 248

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (6-nitro-3-quinolyl)

Except for replacing 3-bromoquinoline with 6-nitro-3-bromoquinoline, the procedure of Example 247 is followed to prepare the title compound. High resolution FAB MS: calculated m / e = 809.3973 for (M + H) ⁺ in C ₄₂ H ₅₇ N ₄ O ₁₂ ; Found m / e = 809.3966.

Example 249

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-phenyl

Except for replacing 3-bromoquinoline with iodobenzene, the procedure of Example 247 is followed to prepare the title compound. High resolution FAB MS: calculated m / e = 713.4013 for (M + H) ⁺ of C ₃₉ H ₅₇ N ₂ O ₁₀ ; Found m / e = 713.3998.

Example 250

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-naphthyl

The procedure of Example 247 is carried out except that 3-bromoquinoline is replaced by 1-iodonaphthalene to prepare the title compound. High resolution FAB MS: calculated m / e = 763.4170 for (M + H) ⁺ in C ₄₃ H ₅₉ N ₂ O ₁₀ ; Found m / e = 763.4161.

Example 251

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (2-naphthyl)

Except for replacing 3-bromoquinoline with 2-bromonaphthalene, the procedure of Example 247 is followed to prepare the title compound. High resolution FAB MS: calculated m / e = 763.4170 for (M + H) ⁺ in C ₄₃ H ₅₉ N ₂ O ₁₀ ; Found m / e = 763.4150.

Example 252

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (6-methoxy-2-naphthyl)

Except for replacing 3-bromoquinoline with 6-methoxy-2-bromonaphthalene, the procedure of Example 247 is followed to prepare the title compound. High resolution FAB MS: calculated m / e = 793.4275 for (M + H) ⁺ in C ₄₄ H ₆₁ N ₂ O ₁₁ ; Found m / e = 793.4256.

Example 253

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (6-chloro-2-naphthyl)

The procedure of Example 247 is carried out except that 3-bromoquinoline is replaced with 6-chloro-3-bromoquinoline to prepare the title compound. High resolution FAB MS: calculated m / e = 798.3732 for (M + H) ⁺ of C ₄₂ H ₅₇ N ₃ O ₁₀ Cl; Found m / e = 798.3743.

Example 254

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (6-quinolyl)

The procedure of Example 247 is carried out except that 3-bromoquinoline is replaced with 6-bromoquinoline to prepare the title compound. High resolution FAB MS: calculated m / e = 764.4122 for (M + H) ⁺ of C ₄₂ H ₅₈ N ₃ O ₁₀ ; Found m / e = 764.4116.

Example 255

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (2-methyl-6-quinolyl)

The procedure of Example 247 is carried out except that 3-bromoquinoline is replaced with 6-bromo-2-methylquinoline to prepare the title compound. High resolution FAB MS: calculated m / e = 778.4279 for (M + H) ⁺ in C ₄₃ H ₆₀ N ₃ O ₁₀ ; Found m / e = 778.4282.

Example 256

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (5- (N- (2-pyridyl) amino) carbonyl) furanyl)

The procedure of Example 247 is carried out except that 3-bromoquinoline is replaced with 5-bromo-furan-2-carboxylic acid pyridin-2-yl amide to prepare the title compound. MS (FAB +): m / e 823 for (M + H) ⁺ .

Example 257

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (1-phenylethenyl)

Except for replacing 3-bromoquinoline with α-bromostyrene, the procedure of Example 247 is followed to prepare the title compound. MS (ESI) m / e 739 (M + H) ⁺ .

Example 258

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-Br

Step 258a: Compound 6E from Scheme 1c; R is -CH ₂ -C≡C-Br

To a nitrogenous solution of Example 246, compound from Step h (100 mg) in acetone (1 ml) is added acetic acid (8.4 μl) at ambient temperature. A second solution containing N-bromosuccinimide (39 mg) and silver nitrate (2.5 mg) in 1 ml of acetone was prepared and then stirred at room temperature under nitrogen for 10 minutes and cooled to 0 ° C. The first solution is then added in one portion to the second solution, the cooling bath is removed, and the resulting reaction mixture is stirred at room temperature under nitrogen for 2 hours. The reaction is then diluted with ethyl acetate and saturated aqueous sodium bicarbonate is added and the mixture is stirred at rt overnight. The organic phase is separated, washed with brine and dried (MgSO ₄ ). The solvent is removed and the residue is purified by chromatography on silica gel, eluting with 40% acetone / hexane to afford the title compound (50 mg, 46%).

Step 258b: compound of Formula 9; L is CO, T is NH and R is -CH ₂ -C≡C-Br

Compound sample (35 mg) from step 258a is dissolved in methanol (2 ml) and stirred at ambient temperature for 16 hours. The solvent is removed and the residue is purified by chromatography on silica gel eluting with 5: 94: 1 methanol / dichloromethane / 1% NH ₄ OH to afford the title compound (32 mg, 26%). MS (ESI) m / e 715 (M + H) ⁺ .

Example 259

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -(2,2-dimethyl-1,3-dioxolan-4-yl)

Step 259a: Compound 6D from Scheme 1c; R is -CH ₂ -CH (OH) CH ₂ OH and R ^p Is acetyl

Example 176, Sample compound from step d (5.0 g, 7.32 mmol; Compound 6D from Scheme 1c in which R is -CH ₂ CH = CH ₂ and R ^p is acetyl) and N-methyl in THF (25 ml) at room temperature OsO ₄ (4% in H ₂ O, 0.090 ml, 0.0147 mmol) is added to morpholine N oxide (1.7 g, 14.5 mmol) and the mixture is stirred for 24 hours. The reaction is quenched with sodium bisulfite (1.5 g), water (10 ml) and the solvent is removed in vacuo. The residue is dissolved in ethyl acetate, which is washed with saturated aqueous sodium bicarbonate, water and brine and then dried (Na ₂ SO ₄ ). Remove the solvent to afford the title compound (3.17 g).

Step 259b: Compound 6D from Scheme 1c; R is -CH ₂ -(2,2-dimethyl-1,3-dioxolan-4-yl) and R ^p Is acetyl and R ^d Is H

To compound sample (500 mg, 0.70 mmol) and 2,2-dimethoxypropane (0.26 ml, 2.1 mmol) from step 259a in toluene (7 ml) was added p-toluenesulfonic acid (160 mg, 0.84 mmol) and the mixture was 55 ° C. Stir for 3 days. The mixture is diluted with ethyl acetate and the solution is washed with 10% sodium carbonate solution, water and brine. Dry the organic phase (Na ₂ SO ₄ ) and remove the solvent to afford the crude product, which was purified by chromatography on silica gel eluting with 2: 97: 1 methanol / chloroform / ammonium hydroxide to give the title compound (363 mg). To obtain.

Step 259c: Compound 6E from Scheme 1c; R is -CH ₂ -(2,2-dimethyl-1,3-dioxolan-4-yl) and R ^p Is acetyl and R ^d Is H

Following the procedure of Example 1, step f, the sample of compound (356 mg, 0.47 mmol) from step 259b was oxidized with N-chlorosuccinimide and dimethylsulfide to give the title compound (371 mg).

Step 259d: a compound of Formula 9; L is CO, T is NH and R is -CH ₂ -(2,2-dimethyl-1,3-dioxolan-4-yl)

Sample of compound (100 mg, 0.13 mmol) from step 259c is stirred overnight in methanol (4 ml) at room temperature. The solvent is removed and the residue is purified by chromatography on silica gel eluting with 0.9: 98: 1 methanol / chloroform / ammonium hydroxide to afford the title compound (87 mg). MS m / e 713 (M + H) ⁺ .

Example 260

A compound of formula 9; L is CO, T is NH and R is -CH ₂ CH (OH) CH ₂ OH

Samples of compounds from Example 259 (100 mg, 0.13 mmol) are stirred for 3 h under reflux with p-toluenesulfonic acid (35 mg, 0.18 mmol) in 4: 1 THF / water (2.5 ml). The mixture is diluted with ethyl acetate and the solution is washed with 10% sodium carbonate solution, water and brine. Dry the organic phase (Na ₂ SO ₄ ) and remove the solvent to afford the crude product, which was purified by chromatography on silica gel eluting with 2: 97: 1 methanol / chloroform / ammonium hydroxide to give the title compound (61 mg). To obtain. MS m / e 689 (M + H) ⁺ .

Example 261

A compound of formula 9; L is CO, T is NH and R is -CH ₂ CH (OH) -phenyl

To a sample of the compound from Example 220 (550 mg, 0.87 mmol) in dry THF (16 ml) under nitrogen at 0 ° C. was added a solution of phenyl magnesium bromide (3.0 M, 2.0 ml, 6.0 mmol) in ether. The mixture is stirred for about 1 hour and the reaction is quenched with saturated ammonium chloride solution. The mixture is extracted with ethyl acetate and the solution is washed with water and brine and then dried (Na ₂ SO ₄ ). The solvent is removed and the residue is purified by chromatography on silica gel eluting with 10: 90: 0.5 methanol / dichloromethane / ammonium hydroxide to afford the title compound (235 mg) as two isomers. Isomer A: MS m / e 719 (M + H) ⁺ . Isomer B: MS m / e 719 (M + H) ⁺ .

Example 262

A compound of formula 9; L is CO and T is N (NH ₂ ) And R is -CH ₂ CH = CH ₂ to be

To a sample of compound (793 mg, 1.0 mmol) from Example 102, step b in 9: 1 acetonitrile / water (10 ml) is added hydrazine (85% aqueous solution, 0.50 ml, 10.0 mmol). The mixture is stirred at room temperature under nitrogen for 4 days. The mixture is diluted with ethyl acetate and the organic phase is washed with water and brine and then dried (Na ₂ SO ₄ ). The solvent was removed and the residue was purified by chromatography on silica gel eluting with 5: 95: 0.5 methanol / chloroform / ammonium hydroxide to afford the title compound (91 mg). MS m / e 654 (M + H) ⁺ .

Example 263

A compound of formula 9; L is CO and T is N (NH ₂ ) And R is -CH ₂ -CH = CH- (3-quinolyl)

The title compound is prepared by following the procedure of Example 178 except that the compound from Example 177 is replaced with the compound from Example 262. MS m / e 781 (M + H) ⁺ . High resolution FAB MS: m / e = 781.4176, calculated for (M + H) ⁺ of C ₄₂ H ₅₉ N ₃ O ₁₀ ; Found m / e = 781.4188.

Example 264

A compound of formula 9; L is CO and T is N (NH ₂ ) And R is -CH ₂ -CH ₂ CH ₂ -(3-quinolyl)

The title compound is prepared by following the procedure of Example 3 except that the compound from Example 3 is replaced with the compound from Example 262. MS m / e 768 (M + H) ⁺ . High resolution FAB MS: m / e = 768.4435 calculated for (M + H) ⁺ in C ₄₂ H ₆₁ N ₃ O ₁₀ ; Found m / e = 768.4437.

Example 265

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH-naphthyl

The procedure of Example 178 is carried out except that 3-bromoquinoline of Example 178 is replaced with 1-bromonaphthalene to prepare the title compound. MS m / e 764 (M + H) ⁺ .

Example 266

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3- (2-furanyl) -6-quinolyl)

2'-acetylated derivative of the compound of Example 219 in anhydrous toluene (Example 177, acetylated by the procedure of step a) Sample (177 mg, 0.200 mmol), 2- (tributylstannyl) furan (78 μL, 0.200 mmol) and Pd (triphenylphosphine) ₄ (23 mg, 0.020 mmol) are heated in a closed tube at 60-90 ° C. for 20 hours. The mixture is diluted with ethyl acetate and washed with 5% aqueous sodium bicarbonate and brine and then dried (Na ₂ SO ₄ ). The solvent is removed and the residue is purified by chromatography on silica gel, eluting with 1: 1 acetone / hexane to afford the acetylated title compound. The material is stirred with methanol for 48 hours and the solvent is removed. The residue is purified by chromatography on silica gel eluting with 95: 5: 0.5 dichloromethane / methanol / dimethylamine to give the title compound (102 mg). MS m / e 832 (M + H) ⁺ . High resolution FAB MS: m / e = 832.4384 calculated for (M + H) ⁺ in C ₄₆ H ₆₁ N ₃ 0 ₁₁ ; Found m / e = 832.4384.

Example 267

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (8-chloro-3-quinolyl)

The procedure of Example 178 is carried out except that the 3-bromoquinoline of Example 178 is replaced with 8-chloro-3-bromoquinoline, to prepare the title compound. MS m / e 800 (M + H) ⁺ . High resolution FAB MS: m / e = 800.3889 calculated for (M + H) ⁺ in C ₄₂ H ₅₈ ClN ₃ O ₁₀ ; Found m / e = 800.3890.

Example 268

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (4-chloro-2-trifluoromethyl-6-quinolyl)

The procedure of Example 178 is carried out except that the 3-bromoquinoline of Example 178 is replaced with 6-bromo-4-chloro-2-trifluoromethylquinoline, to prepare the title compound. MS m / e 868 (M + H) ⁺ .

Example 269

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (2-fluorenyl)

The procedure of Example 178 is carried out except that 3-bromoquinoline of Example 178 is replaced with 2-bromofluorene to prepare the title compound. MS m / e 803 (M + H) ⁺ .

Example 270

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (9-fluorenon-2-yl)

The procedure of Example 178 is carried out except that the 3-bromoquinoline of Example 178 is replaced with 2-iodo-9-fluororenone, to prepare the title compound. MS m / e 817 (M + H) ⁺ . Elemental Analysis for C ₄₆ H ₆₀ N ₂ O ₁₁ : Calculated: C, 67.63; H, 7. 40; N, 3.43; Found: C, 68.11; H, 8.08; N, 3.21.

Example 271

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6-benzoyl-2-naphthyl)

Replace 3-bromoquinoline of Example 178 with 6-benzoyl-2- (trifluoromethylsulfonyloxy) naphthalene (prepared by reacting 6-benzoyl-2-naphthol with trifluoromethylsulfonic anhydride) The procedure of Example 178 is carried out except that the title compound is prepared. MS m / e 869 (M + H) ⁺ .

Example 272

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (7-methoxy-2-naphthyl)

3-bromoquinoline of Example 178 7-methoxy-2- (trifluoromethylsulfonyloxy) naphthalene (prepared by reacting 7-methoxy-2-naphthol with trifluoromethylsulfonic anhydride) Except for replacing with the procedure of Example 178 to prepare the title compound. MS m / e 795 (M + H) ⁺ . Elemental analysis for C ₄₄ H ₆₂ N ₂ O ₁₁ .0.5H ₂ O: calcd: C, 65.73; H, 7.90; N, 3.48; Found: C, 65.62; H, 8.06; N, 3.49.

Example 273

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3-phenyl-6-quinolyl)

2'-acetylated derivative of the compound of Example 219 in dioxane (2 ml) (Example 177, acetylated by the procedure of step a) Sample (177 mg, 0.200 mmol), Pd (triphenylphosphine) ₄ (11.5 mg, 0.010 mmol), a mixture of CuBr (1.43 mg) and (tributylstannyl) benzene (78.3 μl) are heated in a sealed tube at 100 ° C. for 15 hours. The mixture is diluted with ethyl acetate and washed with 5% aqueous sodium carbonate and brine and then dried (Na ₂ SO ₄ ). The solvent is removed and the residue is purified by chromatography on silica gel to give the acetylated title compound (77 mg). The material is stirred with methanol for 48 hours and the solvent is removed. The residue is purified by chromatography on silica gel to give the title compound (54.2 mg). MS m / e 842 (M + H) ⁺ .

Example 274

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3- (2-pyridyl) -6-quinolyl)

The title compound is prepared by following the procedure of Example 273 except for replacing the 2- (tributylstannyl) furan of Example 273 with 2- (tributylstannyl) pyridine. MS m / e 841 (M + H) ⁺ .

Example 275

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3- (2-thiophenyl) -6-quinolyl)

The title compound is prepared by following the procedure of Example 273 except for replacing the 2- (tributylstannyl) furan of Example 273 with 2- (tributylstannyl) thiophene. MS m / e 848 (M + H) ⁺ .

Example 276

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (4-methylnaphthyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replacing the 3-bromoquinoline of Example 178 with 1-bromo-4-methylnaphthalene Except for the procedure of Example 178 to prepare the title compound. MS m / e 779 (M + H) ⁺ . High resolution FAB MS: m / e = 779.4483 calculated for (M + H) ⁺ in C ₄₄ H ₆₂ N ₂ O ₁₀ ; Found m / e = 779.4495.

Example 277

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6-β-D-galactopyranosyl-2-naphthyl)

Replace the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replace the 3-bromoquinoline of Example 178 with 6-bromo-2-naphthyl-β-D The title compound is prepared by following the procedure of Example 178 except for replacing with galactopyranoside (commercially available from Sigma Aldrich). MS m / e 943 (M + H) ⁺ .

Example 278

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (7-quinolyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, and replacing the 3-bromoquinoline of Example 178 with 7- (trifluorosulfonyl) quinoline Except for the procedure of Example 178 to prepare the title compound. MS m / e 766 (M + H) ⁺ .

Example 279

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (4-fluoronaphthyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replacing the 3-bromoquinoline of Example 178 with 1-bromo-4-fluoronaphthalene Except for the procedure of Example 178 to prepare the title compound. MS m / e 783 (M + H) ⁺ . High resolution FAB MS: m / e = 783.4227 calculated for (M + H) ⁺ in C ₄₃ H ₅₉ FN ₂ O ₁₀ ; Found m / e = 783.4223.

Example 280

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3-biphenyl)

Except that the 2'-acetylated compound of Example 177 is replaced by the 2'-benzoylated compound of Example 102, step c and the 3-bromoquinoline of Example 178 is replaced by 3-bromobiphenyl The procedure of Example 178 is performed to prepare the title compound. MS m / e 791 (M + H) ⁺ . High resolution FAB MS: m / e = 791.4483 calculated for (M + H) ⁺ in C ₄₅ H ₆₃ N ₂ O ₁₀ ; Found m / e = 791.4492.

Example 281

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (5-nitronaphthyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replacing the 3-bromoquinoline of Example 178 with 1-bromo-5-nitronaphthalene Except for the procedure of Example 178 to prepare the title compound.

Example 282

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (4-pyrrolylphenyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, and replacing the 3-bromoquinoline of Example 178 with 1- (4-iodophenyl) pyrrole Except for the procedure of Example 178 to prepare the title compound. MS m / e 780 (M + H) ⁺ . High resolution FAB MS: m / e = 780.4430 calculated for (M + H) ⁺ in C ₄₃ H ₆₁ N ₃ O ₁₀ ; Found m / e = 780.4424.

Example 283

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6-methoxy-2-naphthyl)

Replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replacing the 3-bromoquinoline of Example 178 with 2-bromo-6-methoxynaphthalene Except for the procedure of Example 178 to prepare the title compound. MS m / e 795 (M + H) ⁺ . High resolution FAB MS: m / e = 795.4426 calculated for (M + H) ⁺ for C ₄₄ H ₆₂ N ₂ 0 ₁₁ ; Found m / e = 795.4426.

Example 284

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (3,5-dichlorophenyl)

Replace the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replace the 3-bromoquinoline of Example 178 with 1,3-dichloro-5-iodobenzene The procedure of Example 178 is carried out except that the title compound is prepared. MS m / e 783 (M + H) ⁺ . High resolution FAB MS: m / e = 783.3390 calculated for (M + H) ⁺ for C ₃₉ H ₅₇ Cl ₂ N ₂ O ₁₀ ; Found m / e = 783.3392.

Example 285

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -(3-iodophenyl)

Example 1, except that allyl bromide of step a was replaced with 3-iodobenzyl bromide, the procedure of Example 1, steps a to f was followed to yield compound 9 from Scheme 1b, wherein R is 3- Iodophenylmethyl and R ^p is benzoyl), which is treated with the compound according to the procedure of Example 102 to give the title compound. MS m / e 815 (M + H) ⁺ .

Example 286

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -(3- (2-furanyl) phenyl)

Except for replacing the compound of Example 265 with the compound of Example 285, the procedure of Example 266 is performed to prepare the title compound. MS m / e 689 (M + H) ⁺ .

Example 287

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6-hydroxy-2-naphthyl)

Except for replacing the 2'-acetylated compound of Example 177 with the 2'-benzoylated compound of Example 102, step c and replacing the 3-bromoquinoline of Example 178 with 6-bromo-2-naphthol Then the procedure of Example 178 is carried out to prepare the title compound. MS m / e 781 (M + H) ⁺ .

Example 288

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6- (2-bromoethoxy) -2-naphthyl)

The procedure of Example 178 is carried out except that 3-bromoquinoline of Example 178 is replaced with 6-bromo-2- (2-bromoethoxy) naphthalene, to prepare the title compound. MS m / e 887 (M + H) ⁺ .

Example 289

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH- (6- (2- (tetrazolyl) ethoxy-2-naphthyl)

To a sample of compound from Example 288 (371 mg, 0.4 mmol) in acetonitrile (4 ml) is added tetrazole (138 mg, 2 mmol) and triethylamine (0.556 ml, 4 mmol) and the mixture is heated at 60 ° C. under nitrogen overnight. The volatiles are removed under vacuum and the residue is dissolved in ethyl acetate. The solution is washed with 5% sodium bicarbonate solution and brine, dried (Na ₂ SO ₄ ) and then concentrated. The residue is purified by chromatography on silica gel, eluting with 97: 3: 0.5 dichloromethane / methanol / ammonium hydroxide. The product is stirred in methanol for 2 days at room temperature, then the product is purified by chromatography on silica gel eluting with 99: 1: 0.5 dichloromethane / methanol / ammonium hydroxide. MS m / e 877 (M + H) ⁺ .

Example 290

A compound of formula 9; L is CO and T is NH ₂ And R is -CH ₂ -CH = CH-naphthyl

The procedure of Example 178 is carried out except that 3-bromoquinoline of Example 178 is replaced with 1-bromonaphthalene to prepare the title compound. MS m / e xxx (M + H) ⁺ .

Example 291

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -C≡C- (2-phenylethenyl)

Except for replacing 3-bromoquinoline with beta-bromostyrene, the procedure of Example 247 is followed to prepare the title compound. MS (ESI) m / e 739 (M + H) ⁺ .

Example 292

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -CH = CH- (5- (3-isooxazolyl) -2-thiophenyl)

Step 292a: Compound 37 from Scheme 7; R ^BB Is OH

To 11.8 ml (11.8 mmol) of borane-THF complex (1 mol solution in tetrahydrofuran) at −10 ° C. add 2-methyl-2-butene (2.7 ml, 24 mmol). The reaction is stirred at 0 ° C. for 2 hours and the compound from Example 246, step h, in compound 10E tetrahydrofuran [Compound 6E from Scheme 1c; R ^p is acetyl and R is -CH ₂ -C≡CH, 2 g, 2.95 mmol] is added at once. The reaction is stirred at 0 ° C. for 1 h and warmed to ambient temperature. After 3 hours, the reaction is recooled to 0 ° C. and 5% aqueous sodium carbonate is added. The mixture is extracted with ethyl acetate and the organic layer is washed with brine and then dried over magnesium sulfate. Concentration and drying in vacuo gave 3.6 g of crude product which was purified by silica gel chromatography eluting with acetone / hexane (1: 1) to afford the title compound (0.85 g, 40%).

Step 292b: Compound of Formula 9; L is CO and T is NH and R ^c Is acetyl and R is -CH ₂ -CH = CH- (5- (3-isooxazolyl) -2-thiophenyl)

In a pressure tube equipped with a stir bar, 100 mg (0.138 mmol) of the compound from step 292a, potassium carbonate (42 mg, 0.3 mmol), 2-bromo-5- (isoxazol-3-yl) thiophene (48 mg, 0.21 mmol), palladium (II) acetate (0.15 mg, 0.7 mmol), 0.75 ml of acetone and 0.75 ml of water. The reaction is degassed by performing two freeze-pump-thaw cycles. The reaction tube is then sealed under nitrogen and heated at 65 ° C. for 2 hours. The mixture is diluted with ethyl acetate and washed successively with water and brine. The organic extract is dried over magnesium sulfate and concentrated in vacuo. Dry to high weight under high vacuum to afford 140 mg of crude product.

Step 292c: a compound of Formula 9; L is CO, T is NH and R is -CH ₂ -CH = CH- (5- (3-isooxazolyl) -2-thiophenyl)

Compound (140 mg) from step 292b is dissolved in 5 ml of methanol and the solution is stirred at ambient temperature for 20 hours. The solution is concentrated in vacuo and dried to constant weight. The crude product was purified by silica gel chromatography eluting with 98: 1: 1 dichloromethane / methanol / ammonium hydroxide to afford 34 mg of the title compound. High resolution FAB MS: m / e = 788.3792 calculated for (M + H) ⁺ in C ₄₀ H ₅₈ N ₃ 0 ₁₁ S; Found m / e = 788.3809.

Example 293

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -CH = CH- (1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)

The procedure of Example 292 is carried out except that 2-bromo-5- (isoxazol-3-yl) thiophene is replaced with 5-bromo-1,3-dimethyluracil, to prepare the title compound. . High resolution FAB MS: m / e = 777.4286 calculated for (M + H) ⁺ in C ₃₉ H ₆₁ N ₄ O ₁₂ ; Found m / e = 777.4291.

Example 294

A compound of formula 9; L is CO, T is NH and R is -CH ₂ -CH = CH- (5- (2-pyridyl) aminocarbonyl-2-furanyl)

The procedure of Example 292 is followed except that 2-bromo-5- (isoxazol-3-yl) thiophene is replaced with 5-bromo-furan-2-carboxylic acid pyridin-2-yl-amide To give the title compound. MS (ESI) < + >: m / e at (M + H) ⁺ 825.

According to the present invention, a new class of 6-O-substituted with increased acid stability and enhanced activity against gram negative bacteria and macrolide-resistant gram positive bacteria compared to erythromycin A and 6-O-methyl erythromycin A Erythromycin derivatives can be provided to treat bacterial infections.

Claims (3)

A compound of Formula 4a or a pharmaceutically acceptable salt thereof. Formula 4a In Formula 4a above, R ^c is hydrogen or a hydroxy protecting group, R is   (1) (a) -C≡N,      (b) -F, (c) -S (O) _n R ¹⁰ wherein n is 0, 1 or 2 and R ¹⁰ is C ₁ -C ₃ -alkyl or pe         Neal]      (d) aryl,      (e) substituted aryl,      (f) heteroaryl and      (g) substituted heteroaryl      Methyl substituted with a moiety selected from the group consisting of   (2) (a) halogen,      (b) hydroxy, (c) C ₁ -C ₃ -alkoxy, (d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy, (e) -N ₃ , (f) -O-SO _2- (substituted C ₁ -C ₆ -alkyl), (g) -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are       (Iii) hydrogen, (Ii) C ₁ -C ₁₂ -alkyl, (Iii) substituted C ₁ -C ₁₂ -alkyl, (Iii) C ₃ -C ₁₂ -alkenyl, (Iii) substituted C ₃ -C ₁₂ -alkenyl, (Iii) C ₃ -C ₁₂ -alkynyl, (Iii) substituted C ₃ -C ₁₂ -alkynyl,       (Iii) aryl, (Iii) C ₃ -C ₈ -cycloalkyl, (Iii) substituted C ₃ -C ₈ -cycloalkyl,       (Iii) substituted aryl,       (Vi) heterocycloalkyl,       (Iii) substituted heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with aryl, (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted aryl, (Iii) C ₁ -C ₁₂ -alkyl substituted with heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with C ₃ -C ₈ -cycloalkyl (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted C ₃ -C ₈ -cycloalkyl,       (Iii) heteroaryl,       (Iii) substituted heteroaryl, (Vi) C ₁ -C ₁₂ -alkyl substituted with heteroaryl and (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl      Selected from the group consisting of R ¹³ and R ¹⁴ together with the atoms to which they are attached,       (Iii) halogen,       (Ii) hydroxy, (Iii) C ₁ -C ₃ -alkoxy, (Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,       (Iii) oxo, (Iii) C ₁ -C ₃ -alkyl, (Iii) halo-C ₁ -C ₃ -alkyl and (Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl       3 which may be substituted with one substituent selected from the group consisting of       To form a 10- to 10-membered heterocycloalkyl ring; (h) -CO ₂ R ¹⁰ , wherein R ¹⁰ is as defined above; (i) = NOR ¹⁰ ,      (j) -C ≡N, (k) -OS (O) _n R ¹⁰ ,      (l) aryl,      (m) substituted aryl,      (n) heteroaryl,      (o) substituted heteroaryl, (p) substituted C ₃ -C ₈ -cycloalkyl, (q) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,      (r) heterocycloalkyl and      (s) substituted heterocycloalkyl C ₂ -C ₁₀ -alkyl substituted with one substituent selected from the group consisting of   (3) (a) halogen,      (b) -CHO, (c) -CO ₂ R ¹⁰ , (d) -C (O) -R ⁹ , (e) -C (O) NR ¹¹ R ¹² ,      (f) -C ≡N,      (g) aryl,      (h) substituted aryl,      (i) heteroaryl,      (j) substituted heteroaryl, (k) C ₃ -C ₇ -cycloalkyl and (l) C ₁ -C ₁₂ -alkyl substituted with heteroaryl C ₃ -alkenyl substituted with a residue selected from the group consisting of (4) C ₄ -C ₁₀ -alkenyl,   (5) (a) halogen, (b) C ₁ -C ₃ -alkoxy,      (c) oxo,      (d) -CHO, (e) -CO ₂ R ¹⁰ , (f) -C (O) NR ¹¹ R ¹² , (g) -NR ¹³ R ¹⁴ , (h) = NOR ¹⁰ ,      (i) -C ≡N, (j) -OS (O) _n R ¹⁰ ,      (k) aryl,      (l) substituted aryl,      (m) heteroaryl,      (n) substituted heteroaryl, (o) C ₃ -C ₇ -cycloalkyl, (p) C ₁ -C ₁₂ -alkyl substituted with heteroaryl, (q) -NHC (O) R ¹⁰ , (r) -NHC (O) NR ¹¹ R ¹² , (s) = N-NR ¹³ R ¹⁴ , (t) = NR ⁹ , (u) = N-NHC (O) R ¹⁰ and (v) = N-NHC (O) NR ¹¹ R ¹² C ₄ -C ₁₀ -alke substituted with one substituent selected from the group consisting of      Neil, (6) C ₃ -C ₁₀ -alkynyl and   (7) (a) trialkylsilyl,      (b) aryl,      (c) substituted aryl,      (d) heteroaryl and      (e) substituted heteroaryl Is selected from the group consisting of C ₃ -C ₁₀ -alkynyl substituted with one or more substituents selected from the group consisting of A, B, D and E   (a) hydrogen,   (b) (iii) aryl,       (Ii) substituted aryl,       (Iii) heteroaryl,       (Iii) substituted heteroaryl,       (Iii) heterocycloalkyl,       (Iii) hydroxy, (Iii) C ₁ -C ₆ -alkoxy,       (Iii) Br, Cl, F or I and (Iii) -NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are as defined above;       Substituted with one or more substituents selected from the group consisting of Unsubstituted C ₁ -C ₆ -alkyl, (c) C ₃ -C ₇ -cycloalkyl,   (d) aryl,   (e) substituted aryl,   (f) heteroaryl,   (g) substituted heteroaryl,   (h) heterocycloalkyl and (i) a group from (b) above substituted with -MR ⁹ Are independently selected from the group consisting of provided that at least two of A, B, D and E are hydrogen, One of the AB, AD, AE, BD, BE or DE pairs, together with the atom (s) to which they are attached, is -O-, -NH-, -N (C ₁ -C ₆ -alkyl-)-, -N (Aryl-C ₁ -C ₆ -alkyl-)-, -N (substituted aryl-C ₁ -C ₆ -alkyl-)-, -N (heteroaryl-C ₁ -C ₆ -alkyl-)-,- N (substituted heteroaryl-C ₁ -C ₆ -alkyl-)-, -S-, -S (O) _n- , -C (O) -NH-, -C (O) -NR ¹² -,- To form a 3- to 7-membered ring with or without a heterofunctional group selected from the group consisting of NH-C (O)-, -NR ¹² -C (O)-and -C (= NH) -NH-, In the above substituent definition,     Aryl is a group selected from the group consisting of phenyl, biphenyl and naphthyl     ego, Substituted aryl has 1, 2 or 3 hydrogen atoms of Cl, F, I, OH, CN, C _1- C ₃ -alkyl, C ₁ -C ₆ -alkoxy, amino, dialkylamino, nitro, carboxaldehyde,     Carboxy, alkoxycarbonyl, carboxamide, phenyl, biphenyl, naphthyl, pyridyl,     Pyrimidinyl, quinolyl, imidazolyl, oxazolyl, isoxoxazolyl, thiophenyl,     By a substituent selected from the group consisting of furanyl and isoquinolinyl     Independently substituted phenyl, biphenyl or naphthyl,     Heteroaryl is pyridyl, pyrimidinyl, quinolyl, imidazolyl, oxazolyl, iso     From the group consisting of oxazolyl, thiophenyl, furanyl and isoquinolinyl     Is the selected group,     Substituted heteroaryl has 1, 2 or 3 hydrogen atoms selected from Cl, Br, F, OH, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₆ -alkoxy, haloalkyl, amino, dialkylamino, nit     Furnace, carboxy, alkoxycarbonyl, phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl,     Quinolyl, imidazolyl, oxazolyl, isoxoxazolyl, thiophenyl, furanyl and these     Independently by substituents selected from the group consisting of soquinolinyl     Substituted pyridyl, pyrimidinyl, quinolyl, imidazolyl, oxazolyl, isoxazole     Reel, thiophenyl, furanyl or isoquinolinyl. A pharmaceutical composition for inhibiting bacterial infection, comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier. A method of preparing a compound of Formula 4a, including the step of treating a compound of Formula 4 with a reducing agent: Formula 4 Formula 4a In the above formulas 4 and 4a, R ^c is hydrogen or a hydroxy protecting group, R is   (1) (a) -C≡N,      (b) -F, (c) —S (O) _n R ¹⁰ where n is 0, 1 or 2 and R ¹⁰ is C ₁ -C ₃ -alkyl or phenyl;      (d) aryl,      (e) substituted aryl,      (f) heteroaryl and      (g) substituted heteroaryl      Methyl substituted with a moiety selected from the group consisting of   (2) (a) halogen,      (b) hydroxy, (c) C ₁ -C ₃ -alkoxy, (d) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy, (e) -N ₃ , (f) -O-SO _2- (substituted C ₁ -C ₆ -alkyl), (g) -NR ¹³ R ¹⁴ wherein R ¹³ and R ¹⁴ are       (Iii) hydrogen, (Ii) C ₁ -C ₁₂ -alkyl, (Iii) substituted C ₁ -C ₁₂ -alkyl, (Iii) C ₃ -C ₁₂ -alkenyl, (Iii) substituted C ₃ -C ₁₂ -alkenyl, (Iii) C ₃ -C ₁₂ -alkynyl, (Iii) substituted C ₃ -C ₁₂ -alkynyl,       (Iii) aryl, (Iii) C ₃ -C ₈ -cycloalkyl, (Iii) substituted C ₃ -C ₈ -cycloalkyl,       (Iii) substituted aryl,       (Vi) heterocycloalkyl,       (Iii) substituted heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with aryl, (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted aryl, (Iii) C ₁ -C ₁₂ -alkyl substituted with heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heterocycloalkyl, (Iii) C ₁ -C ₁₂ -alkyl substituted with C ₃ -C ₈ -cycloalkyl (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted C ₃ -C ₈ -cycloalkyl,       (Iii) heteroaryl,       (Iii) substituted heteroaryl, (Vi) C ₁ -C ₁₂ -alkyl substituted with heteroaryl and (Iii) C ₁ -C ₁₂ -alkyl substituted with substituted heteroaryl       Selected from the group consisting of R ¹³ and R ¹⁴ together with the atoms to which they are attached,       (Iii) halogen,       (Ii) hydroxy, (Iii) C ₁ -C ₃ -alkoxy, (Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkoxy,       (Iii) oxo, (Iii) C ₁ -C ₃ -alkyl, (Iii) halo-C ₁ -C ₃ -alkyl and (Iii) C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl       3 which may be substituted with one substituent selected from the group consisting of       To form a 10- to 10-membered heterocycloalkyl ring; (h) -CO ₂ R ¹⁰ , (i) = NOR ¹⁰ ,      (j) -C ≡N, (k) -OS (O) _n R ¹⁰ ,      (l) aryl,      (m) substituted aryl,      (n) heteroaryl,      (o) substituted heteroaryl, (p) substituted C ₃ -C ₈ -cycloalkyl, (q) C ₁ -C ₁₂ -alkyl substituted with heteroaryl,      (r) heterocycloalkyl and      (s) substituted heterocycloalkyl C ₂ -C ₁₀ -alkyl substituted with one substituent selected from the group consisting of   (3) (a) halogen,      (b) -CHO, (c) -CO ₂ R ¹⁰ , (d) -C (O) -R ⁹ , (e) -C (O) NR ¹¹ R ¹² ,      (f) -C ≡N,      (g) aryl,      (h) substituted aryl,      (i) heteroaryl,      (j) substituted heteroaryl, (k) C ₃ -C ₇ -cycloalkyl and (l) C ₁ -C ₁₂ -alkyl substituted with heteroaryl C ₃ -alkenyl substituted with a residue selected from the group consisting of (4) C ₄ -C ₁₀ -alkenyl,   (5) (a) halogen, (b) C ₁ -C ₃ -alkoxy,      (c) oxo,      (d) -CHO, (e) -CO ₂ R ¹⁰ , (f) -C (O) NR ¹¹ R ¹² , (g) -NR ¹³ R ¹⁴ , (h) = NOR ¹⁰ ,      (i) -C ≡N, (j) -OS (O) _n R ¹⁰ ,      (k) aryl,      (l) substituted aryl,      (m) heteroaryl,      (n) substituted heteroaryl, (o) C ₃ -C ₇ -cycloalkyl, (p) C ₁ -C ₁₂ -alkyl substituted with heteroaryl, (q) -NHC (O) R ¹⁰ , (r) -NHC (O) NR ¹¹ R ¹² , (s) = N-NR ¹³ R ¹⁴ , (t) = NR ⁹ , (u) = N-NHC (O) R ¹⁰ and (v) = N-NHC (O) NR ¹¹ R ¹² C ₄ -C ₁₀ -substituted with one or more substituents selected from the group consisting of      Alkenyl, (6) C ₃ -C ₁₀ -alkynyl and   (7) (a) trialkylsilyl,      (b) aryl,      (c) substituted aryl,      (d) heteroaryl and      (e) substituted heteroaryl Is selected from the group consisting of C ₃ -C ₁₀ -alkynyl substituted with one or more substituents selected from the group consisting of A, B, D and E   (a) hydrogen,   (b) (iii) aryl,       (Ii) substituted aryl,       (Iii) heteroaryl,       (Iii) substituted heteroaryl,       (Iii) heterocycloalkyl,       (Iii) hydroxy, (Iii) C ₁ -C ₆ -alkoxy,       (Iii) Br, Cl, F or I and (Iii) -NR ⁷ R ⁸ , wherein R ⁷ and R ⁸ are hydrogen and C ₁ -C ₆ -alkyl Independently selected from R ⁷ and R ⁸ are the nitrogen atoms to which they are linked       Together to form a 3 to 7 membered ring, wherein the ring is a 5 to 7 membered ring. Right, -O-, -NH-, -N (C ₁ -C ₆ -alkyl-)-, -N (aryl)-, -N (aryl-C ₁ -C ₆ -alkyl-)-, -N (substituted aryl-C ₁ -C ₆ -alkyl-)-, -N (heteroaryl)-, -N (heteroaryl-C _1- C ₆ -alkyl-)-, -N (substituted heteroaryl-C ₁ -C ₆ -alkyl-)-, -S- and -S (O) _n- (F       Wherein n is 1 or 2)       May contain ridges]       Substituted with one or more substituents selected from the group consisting of Unsubstituted C ₁ -C ₆ -alkyl, (c) C ₃ -C ₇ -cycloalkyl,   (d) aryl,   (e) substituted aryl,   (f) heteroaryl,   (g) substituted heteroaryl,   (h) heterocycloalkyl and (i) a group selected from (b) above further substituted with -MR ⁹   Are independently selected from the group consisting of provided that at least two of A, B, D and E are hydrogen, One of the AB, AD, AE, BD, BE or DE pairs, together with the atom (s) to which they are attached, is -O-, -NH-, -N (C ₁ -C ₆ -alkyl-)-, -N (Aryl-C ₁ -C ₆ -alkyl-)-, -N (substituted aryl-C ₁ -C ₆ -alkyl-)-, -N (heteroaryl-C ₁ -C ₆ -alkyl-)-,- N (substituted heteroaryl-C ₁ -C ₆ -alkyl-)-, -S-, -S (O) _n- , -C (O) -NH-, -C (O) -NR ¹² -,- To form a 3- to 7-membered ring with or without a heterofunctional group selected from the group consisting of NH-C (O)-, -NR ¹² -C (O)-and -C (= NH) -NH-, In the above substituent definition,     Aryl is a group selected from the group consisting of phenyl, biphenyl and naphthyl     ego, Substituted aryl has 1, 2 or 3 hydrogen atoms of Cl, F, I, OH, CN, C _1- C ₃ -alkyl, C ₁ -C ₆ -alkoxy, amino, dialkylamino, nitro, carboxaldehyde,     Carboxy, alkoxycarbonyl, carboxamide, phenyl, biphenyl, naphthyl, pyridyl,     Pyrimidinyl, quinolyl, imidazolyl, oxazolyl, isoxoxazolyl, thiophenyl,     By a substituent selected from the group consisting of furanyl and isoquinolinyl     Independently substituted phenyl, biphenyl or naphthyl,     Heteroaryl is pyridyl, pyrimidinyl, quinolyl, imidazolyl, oxazolyl, iso     From the group consisting of oxazolyl, thiophenyl, furanyl and isoquinolinyl     Is the selected group,     Substituted heteroaryl has 1, 2 or 3 hydrogen atoms selected from Cl, Br, F, OH, CN, C ₁ -C ₃ -alkyl, C ₁ -C ₆ -alkoxy, haloalkyl, amino, dialkylamino, nit     Furnace, carboxy, alkoxycarbonyl, phenyl, biphenyl, naphthyl, pyridyl, pyrimidinyl,     Quinolyl, imidazolyl, oxazolyl, isoxoxazolyl, thiophenyl, furanyl and these     Independently by substituents selected from the group consisting of soquinolinyl     Substituted pyridyl, pyrimidinyl, quinolyl, imidazolyl, oxazolyl, isoxazole     Reel, thiophenyl, furanyl or isoquinolinyl.